Thalamus: aspekti ALS

(1)  https://www.ncbi.nlm.nih.gov/pubmed/?term=ALS%2C+thalamus

Brain Pathol. 2018 Jan;28(1):14-27. doi: 10.1111/bpa.12467. Epub 2017 Mar 22.

Neurodegeneration and NLRP3 inflammasome expression in the anterior thalamus of SOD1(G93A) ALS mice.

Debye B¹, Schmülling L¹, Zhou L², Rune G², Beyer C¹, Johann S¹. Abstract

Nowadays, amyotrophic lateral sclerosis (ALS) is considered as a multisystem disorder, characterized by a primary degeneration of motor neurons as well as neuropathological changes in non-motor regions. Neurodegeneration in subcortical areas, such as the thalamus, are believed to contribute to cognitive and behavioral abnormalities in ALS patients. In the present study, we investigated neurodegenerative changes including neuronal loss and glia pathology in the anterodorsal thalamic nucleus (AD) of SOD1(G93A) mice, a widely used animal model for ALS. We detected massive dendrite swelling and neuronal loss in SOD1(G93A) animals, which was accompanied by a mild gliosis. Furthermore, misfolded SOD1 protein and autophagy markers were accumulating in the AD.
Since innate immunity and activation inflammasomes seem to play a crucial role in ALS, we examined protein expression of Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) and the cytokine interleukin 1 beta (IL1β) in AD glial cells and neurons. NLRP3 and ASC were significantly up-regulated in the AD of SOD1(G93A) mice. Finally, co-localization studies revealed expression of NLRP3, ASC and IL1β in neurons. Our study yielded two main findings: (i) neurodegenerative changes already occur at an early symptomatic stage in the AD and (ii) increased inflammasome expression may contribute to neuronal cell death. In conclusion, neurodegeneration in the anterior thalamus may critically account for cognitive changes in ALS pathology.

(2)

Front Aging Neurosci. 2018 Mar 15;10:45. doi: 10.3389/fnagi.2018.00045. eCollection 2018.

Atrophy in the Thalamus But Not Cerebellum Is Specific for C9orf72 FTD and ALS Patients - An Atlas-Based Volumetric MRI Study. Schönecker S¹, Neuhofer C¹, Otto M², Ludolph A², Kassubek J², Landwehrmeyer B², Anderl-Straub S², Semler E², Diehl-Schmid J³, Prix C¹, Vollmar C¹, Fortea J⁴; Deutsches FTLD-Konsortium, Huppertz HJ⁵, Arzberger T⁶, Edbauer D^7,8,9, Feddersen B¹⁰, Dieterich M^1,7,9, Schroeter ML^11,12, Volk AE¹³, Fließbach K^14,15, Schneider A^14,15, Kornhuber J¹⁶, Maler M¹⁶, Prudlo J^17,18, Jahn H^19,20, Boeckh-Behrens T²¹, Danek A¹, Klopstock T^7,9,22, Levin J^1,7. Collaborators (4) Abstract

Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82. Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD.

KEYWORDS:

C9orf72; amyotrophic lateral sclerosis; atlas based volumetric MRI analysis; cerebellum; frontotemporal dementia; salience network; thalamus

PMID:

29599716

PMCID:

PMC5863593

DOI:

10.3389/fnagi.2018.00045

Free PMC Article

 

3) 

Transl Psychiatry. 2019 Jan 31;9(1):54. doi: 10.1038/s41398-019-0381-1.

FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations.

Diehl-Schmid J¹, Licata A², Goldhardt O², Förstl H², Yakushew I³, Otto M⁴, Anderl-Straub S⁴, Beer A⁴, Ludolph AC⁴, Landwehrmeyer GB⁴, Levin J^5,6, Danek A⁵, Fliessbach K^7,8, Spottke A^8,9, Fassbender K¹⁰, Lyros E¹⁰, Prudlo J¹¹, Krause BJ¹², Volk A¹³, Edbauer D^6,14, Schroeter ML^15,16, Drzezga A^17,18, Kornhuber J¹⁹, Lauer M²⁰; FTLDc Study Group, Grimmer T².Collaborators (15)

Abstract

C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, ¹⁸F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.

PMID:

30705258

PMCID:

PMC6355852

DOI:

10.1038/s41398-019-0381-1

[Indexed for MEDLINE]

Free PMC Article

• 
  

ihmisen WIPI genejä löytyy 4 : (WD-repeat domain phosphoinostitide (PI) interacting 1-4)

Search results

Items: 4

• Showing Current items.

Name/Gene ID	Description	Location	Aliases	MIM
Select item 55062 WIPI1 ID: 55062	WD repeat domain, phosphoinositide interacting 1 [Homo sapiens (human)]	Chromosome 17, NC_000017.11 (68421281..68457524, complement)	ATG18, ATG18A, WIPI49	609224
Select item 26100 WIPI2 ID: 26100	WD repeat domain, phosphoinositide interacting 2 [Homo sapiens (human)]	Chromosome 7, NC_000007.14 (5190233..5233855)	ATG18B, Atg21, CGI-50, IDDSSA, WIPI-2	609225
Select item 11152 WDR45 ID: 11152	WD repeat domain 45 [Homo sapiens (human)]	Chromosome X, NC_000023.11 (49074433..49101121, complement)	JM5, NBIA4, NBIA5, WDRX1, WIPI-4, WIPI4	300526
Select item 56270 WDR45B ID: 56270	WD repeat domain 45B [Homo sapiens (human)]	Chromosome 17, NC_000017.11 (82614562..82648530, complement)	NEDSBAS, WDR45L, WIPI-3, WIPI3	609226

WIPI4 (xp11.23), JM5, NBIA4, NBIA5, WDRX1, WIPI-4, autofagiageeni, raudan käsittely hermostossa

Official Symbol

WDR45provided by HGNC

Official Full Name

WD repeat domain 45provided by HGNC

Also known as

JM5; NBIA4; NBIA5; WDRX1; WIPI4; WIPI-4

Summary

This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene has a pseudogene at chromosome 4q31.3. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity and full-length nature of some variants have not been determined. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in thyroid (RPKM 16.7), adrenal (RPKM 15.8) and 25 other tissues See more

Orthologs

 

Preferred Names

WD repeat domain phosphoinositide-interacting protein 4

Names

WD repeat domain, X-linked 1

WD repeat-containing protein 45

WD45 repeat protein interacting with phosphoinositides 4

neurodegeneration with brain iron accumulation 4, NDIA4

neurodegeneration with brain iron accumulation 5, NDIA5

https://www.ncbi.nlm.nih.gov/protein/NP_001025067.1

Conserved Domains (3) summary

COG2319
Location:9 → 275

WD40; WD40 repeat [General function prediction only]

sd00039
Location:196 → 232

7WD40; WD40 repeat [structural motif]

cl29593
Location:187 → 274

WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from ..

 

Related articles in PubMed

1. Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants. Chen H, et al. Eur J Med Genet, 2019 Feb. PMID 29981852
2. Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45. Carvill GL, et al. Epilepsia, 2018 Jan. PMID 29171013, Free PMC Article
3. Early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase in a boy with beta-propeller protein-associated neurodegeneration. Takano K, et al. Eur J Med Genet, 2017 Oct. PMID 28711740
4. Clinical features of a female with WDR45 mutation complicated by infantile spasms: a case report and literature review. Morikawa M, et al. Brain Dev, 2017 Oct. PMID 28551038
5. Beta-Propeller Protein-Associated Neurodegeneration Gregory A, et al. , 1993. PMID 28211668

See all (39) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. Novel missense mutations in WDR45 were identified in female pediatric patients with developmental delay and/or epilepsy. Arg134Pro and p. Gly168Glu mutations showed accumulation of LC3-containing autophagic structures and enlarged cell volume in HeLa cells.
2. WIPI3 and WIPI4 beta-propellers have roles as scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy
3. This study showed that Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45.
4. This study showed that WDR45 genes account for disease of patients diagnosed with an Neurodegeneration with brain iron accumulation disorder.
5. This study showed the WDR45 mutation complicated by infantile spasms.
6. A rare male patient is reported with mutation in WDR45 and early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase.
7. Inherited WDR45 variants are possible, albeit rare. Hemizygous germline variants in males can be viable, but likely result in a more severe NBIA phenotype.
8. Our findings indicate that hemizygous WDR45 mutations in males lead to severe epileptic encephalopathy.
9. WDR45 mutation is associated with beta-propeller protein-associated neurodegeneration.
10. Genetic analysis for WDR45 revealed that she had a splice site mutation

Submit: New GeneRIF Correction See all GeneRIFs (17)

 

WIPI3, WDR46B, (17q25.3), NEDSBAS , beeta-propellirakenteinen autofagian kotrolloija

https://www.ncbi.nlm.nih.gov/gene/56270

Official Symbol

WDR45Bprovided by HGNC

Official Full Name

WD repeat domain 45Bprovided by HGNC

Also known as

WIPI3; WDR45L; WIPI-3; NEDSBAS

Summary

This gene encodes a member of the WIPI or SVP1 family of WD40 repeat-containing proteins. The protein contains seven WD40 repeats that are thought to fold into a beta-propeller structure that mediates protein-protein interactions, and a conserved motif for interaction with phospholipids. The human genome contains several pseudogenes of this gene. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in testis (RPKM 30.3), esophagus (RPKM 20.3) and 25 other tissues See more

Orthologsmouse all

Preferred Names

WD repeat domain phosphoinositide-interacting protein 3

Names

WD repeat protein 45-like

WD repeat-containing protein 45-like

WD repeat-containing protein 45B

WDR45-like protein

WIPI3 long

WIPI49-like protein

 https://www.ncbi.nlm.nih.gov/protein/NP_062559.2

ORIGIN      
        1 mnllpcnphg ngllyagfnq dhgcfacgme ngfrvyntdp lkekekqefl eggvghveml
       61 frcnylalvg ggkkpkyppn kvmiwddlkk ktvieiefst evkavklrrd rivvvldsmi
      121 kvftfthnph qlhvfetcyn pkglcvlcpn snnsllafpg thtghvqlvd lastekppvd
      181 ipahegvlsc ialnlqgtri atasekgtli rifdtssghl iqelrrgsqa aniycinfnq
      241 daslicvssd hgtvhifaae dpkrnkqssl asasflpkyf sskwsfskfq vpsgspcica
      301 fgtepnavia icadgsyykf lfnpkgecir dvyaqflemt ddkl
//

Related articles in PubMed

1. PtdIns-specific MPR pathway association of a novel WD40 repeat protein, WIPI49. Jeffries TR, et al. Mol Biol Cell, 2004 Jun. PMID 15020712, Free PMC Article
2. WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Proikas-Cezanne T, et al. Oncogene, 2004 Dec 16. PMID 15602573
3. WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Bakula D, et al. Nat Commun, 2017 May 31. PMID 28561066, Free PMC Article
4. Systematic proteomics of the VCP-UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis. Raman M, et al. Nat Cell Biol, 2015 Oct. PMID 26389662, Free PMC Article
5. The sequence of the human genome. Venter JC, et al. Science, 2001 Feb 16. PMID 11181995

See all (17) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. WIPI3 and WIPI4 beta-propellers have roles as scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy

Submit: New GeneRIF Correction

WIPI2(7p22.1). Atg21, ATG18B, CGI-50, IDDSSA. WD-toistojaksoinen fosfoinositidin kanssa interaktion tekevä proteiini2

https://www.ncbi.nlm.nih.gov/gene/26100

Also known as

Atg21; ATG18B; CGI-50; IDDSSA; WIPI-2

Summary

WD40 repeat proteins are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins, such as WIPI2, have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids (Proikas-Cezanne et al., 2004 [PubMed 15602573]).[supplied by OMIM, Mar 2008]

Expression

Ubiquitous expression in testis (RPKM 20.8), brain (RPKM 12.7) and 25 other tissues See more

Orthologs mouse all

Preferred Names

WD repeat domain phosphoinositide-interacting protein 2

Names

WD40 repeat protein interacting with phosphoinositides 2

WIPI49-like protein 2

                     /db_xref="MIM:609225"
ORIGIN      
        1 mnlasqsgea gagqllfanf nqdntevkga sraaglgrra vvwslavgsk sgykffslss
       61 vdkleqiyec tdtedvcive rlfssslvai vslkaprklk vchfkkgtei cnysysntil
      121 avklnrqrli vcleeslyih nirdmkvlht iretppnpag lcalsinndn cylaypgsat
      181 igevqvfdti nlraanmipa hdsplaalaf dasgtklata sekgtvirvf sipegqklfe
      241 frrgvkrcvs icslafsmdg mflsassnte tvhifkletv kekppeeptt wtgyfgkvlm
      301 astsylpsqv temfnqgraf atvrlpfcgh knicslatiq kiprllvgaa dgylymynld
      361 pqeggecalm kqhrldgsle ttneildsas hdcplvtqty gaaagkaytd dlgavggacl
      421 edeasalrld edsehppmil rtd

 Conserved Domains (3) summary

COG2319
Location:37 → 290

WD40; WD40 repeat [General function prediction only]

sd00039
Location:161 → 200

7WD40; WD40 repeat [structural motif]

cl02567
Location:184 → 363

WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from .

Related articles in PubMed

1. mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux. Wan W, et al. Mol Cell, 2018 Oct 18. PMID 30340022
2. Recruitment of TBK1 to cytosol-invading Salmonella induces WIPI2-dependent antibacterial autophagy. Thurston TL, et al. EMBO J, 2016 Aug 15. PMID 27370208, Free PMC Article
3. Fluorescence-based imaging of autophagy progression by human WIPI protein detection. Thost AK, et al. Methods, 2015 Mar. PMID 25462558
4. WIPI β-propellers at the crossroads of autophagosome and lipid droplet dynamics. Pfisterer SG, et al. Biochem Soc Trans, 2014 Oct. PMID 25233424
5. WIPI2b and Atg16L1: setting the stage for autophagosome formation. Wilson MI, et al. Biochem Soc Trans, 2014 Oct. PMID 25233411

See all (41) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

1. Regulation of the intracellular WIPI2 protein level by mTORC1 and HUWE1 is a key determinant of autophagy flux.
2. Results suggest that Optn potentiates LC3-II production and maturation of the phagophore into the autophagosome, by facilitating the recruitment of the Atg12-5-16L1 complex to Wipi2-positive phagophores.
3. Data suggest that, in patients with diabetic kidney disease, urinary excretion of mRNAs for MAP1LC3A, WIPI2, and RB1CC1 is down-regulated as compared to healthy control subjects; these transcripts may serve as urinary autophagy biomarkers. (MAP1LC3A = microtubule associated protein 1 light chain 3; WIPI2 = WD repeat domain phosphoinositide-interacting protein 2; RB1CC1 = RB1 inducible coiled-coil 1)
4. Here the authors show that recruitment of WIPI2, itself essential for anti-bacterial autophagy, is dependent on the localization of catalytically active TBK1 to the vicinity of cytosolic bacteria.
5. The specific autophagosomal localization of both WIPI1 and WIPI2 (refered to as WIPI puncta) has been employed to assess autophagy using fluorescence microscopy methods, such as confocal and live-cell video microscopy
6. Data suggest WIPI1/WIPI2 co-localize with microtubule-associated light chain 3 and autophagy related proteins 2/14L, participate in biogenesis of phagosomes, autophagy, and mobilization of lipids to/from intracellular droplets. [review-like article]
7. WIPI-1 and WIPI-2 are functionally required in mediating the PI3P signal at the onset of autophagy in NB4 cells.
8. Data suggest that WIPI2b directly interacts with dimer of ATG16L1 (autophagy related 16-like 1) and this interaction is linked to production of phosphatidylinositol 3-phosphate in endoplasmic reticulum triggered by autophagosome formation. [REVIEW]
9. WIPI2b binds the membrane surrounding Salmonella and recruits the Atg12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella.
10. A role for WIPI2 in the progression of omegasomes into autophagosomes, is reported.

Submit: New GeneRIF Correction See all GeneRIFs (12)

 

WIPI1 (17q24.2) , ATG18, ATG18A, WPI49 tarjoaa beeta-propellialustaa proteiini-interaktioille.

https://www.ncbi.nlm.nih.gov/gene/55062

Official Symbol

WIPI1provided by HGNC

Official Full Name

WD repeat domain, phosphoinositide interacting 1provided by HGNC

Also known as

ATG18; ATG18A; WIPI49

Summary

This gene encodes a WD40 repeat protein. Members of the WD40 repeat family are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

Expression Ubiquitous expression in placenta (RPKM 11.9), heart (RPKM 11.3) and 25 other tissues See moreOrthologs mouse all

 

Preferred Names

WD repeat domain phosphoinositide-interacting protein 1

Names

WIPI-1 alpha

atg18 protein homolog

 

           ##Evidence-Data-END##
FEATURES             Location/Qualifiers
     source          1..364
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="17"
                     /map="17q24.2"
     Protein         1..364
                     /product="WD repeat domain phosphoinositide-interacting
                     protein 1 isoform b"
                     /note="WD repeat domain phosphoinositide-interacting
                     protein 1; WIPI-1 alpha; atg18 protein homolog"
                     /calculated_mol_wt=39811
     Region          <6 ..180="" class="feature" feature_np_001307701.1_region_0="" note="WD40 domain,</span><span id=" region_name="WD40"> found in a number of eukaryotic proteins that cover a
 wide variety of functions including adaptor/regulatory modules in 
signal transduction, pre-mRNA processing and cytoskeleton assembly; 
typically contains a GH dipeptide 11-24 residues from its N-terminus and
 the WD dipeptide at its C-terminus and is 40 residues long, hence the 
name WD40; between GH and WD lies a conserved core; serves as a stable 
propeller-like platform to which proteins can bind either stably or 
reversibly; forms a propeller-like structure with several blades where 
each blade is composed of a four-stranded anti-parallel b-sheet; 
instances with few detectable copies are hypothesized to form larger 
structures by dimerization; each WD40 sequence repeat forms the first 
three strands of one blade and the last strand in the next blade; the 
last C-terminal WD40 repeat completes the blade structure of the first 
WD40 repeat to create the closed ring propeller-structure; residues on 
the top and bottom surface of the propeller are proposed to coordinate 
interactions with other proteins and/or small ligands; 7 copies of the 
repeat are present in this alignment.; cl25539"
                     /db_xref="CDD:330360"

      Region          63..102
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          107..144
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          154..186
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          192..230
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          238..276
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     CDS             1..364
                     /gene="WIPI1"
                     /gene_synonym="ATG18; ATG18A; WIPI49"
                     /coded_by="NM_001320772.1:267..1361"
                     /note="isoform b is encoded by transcript variant 2"
                     /db_xref="CCDS:CCDS82193.1"
                     /db_xref="GeneID:55062"
                     /db_xref="HGNC:HGNC:25471"
                     /db_xref="MIM:609224"
ORIGIN      
        1 mnvyhfkkgt eicnysyssn ilsirlnrqr llvcleesiy ihnikdmkll ktlldipanp
       61 tglcalsinh snsylaypgs ltsgeivlyd gnslktvcti aahegtlaai tfnasgskla
      121 sasekgtvir vfsvpdgqkl yefrrgmkry vtisslvfsm dsqflcassn tetvhifkle
      181 qvtnsrpeep stwsgymgkm fmaatnylpt qvsdmmhqdr afatarlnfs gqrnictlst
      241 iqklprllva sssghlymyn ldpqdggecv likthsllgs gtteenkend lrpslpqsya
      301 atvarpsass astvpgysed ggalrgevip ehefatgpvc lddenefppi ilcrgnqkgk
      361 tkqs
//

Conserved Domains (2) summary

sd00039
Location:63 → 102

7WD40; WD40 repeat [structural motif]

cl25539
Location:6 → 180

WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from .

Related articles in PubMed

1. Detection of WIPI1 mRNA as an indicator of autophagosome formation. Tsuyuki S, et al. Autophagy, 2014 Mar. PMID 24384561, Free PMC Article
2. Fluorescence-based imaging of autophagy progression by human WIPI protein detection. Thost AK, et al. Methods, 2015 Mar. PMID 25462558
3. WIPI β-propellers at the crossroads of autophagosome and lipid droplet dynamics. Pfisterer SG, et al. Biochem Soc Trans, 2014 Oct. PMID 25233424
4. WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells. Brigger D, et al. Cell Death Dis, 2014 Jul 3. PMID 24991767, Free PMC ArticleAbstract
   Members of the WD-repeat protein interacting with phosphoinositides (WIPI) family are phosphatidylinositol 3-phosphate (PI3P) effectors that are essential for the formation of autophagosomes. Autophagosomes, unique double-membraned organelles, are characteristic for autophagy, a bulk degradation mechanism with cytoprotective and homeostatic function. Both, WIPI-1 and WIPI-2 are aberrantly expressed in several solid tumors, linking these genes to carcinogenesis. We now found that the expression of WIPI-1 was significantly reduced in a large cohort of 98 primary acute myeloid leukemia (AML) patient samples (complex karyotypes; t(8;21); t(15,17); inv(16)). In contrast, the expression of WIPI-2 was only reduced in acute promyelocytic leukemia (APL), a distinct subtype of AML (t(15,17)). As AML cells are blocked in their differentiation, we tested if the expression levels of WIPI-1 and WIPI-2 increase during all-trans retinoic acid (ATRA)-induced neutrophil differentiation of APL. According to the higher WIPI-1 expression in granulocytes compared with immature blast cells, WIPI-1 but not WIPI-2 expression was significantly induced during neutrophil differentiation of NB4 APL cells. Interestingly, the induction of WIPI-1 expression was dependent on the transcription factor PU.1, a master regulator of myelopoiesis, supporting our notion that WIPI-1 expression is reduced in AML patients lacking proper PU-1 activity. Further, knocking down WIPI-1 in NB4 cells markedly attenuated the autophagic flux and significantly reduced neutrophil differentiation. This result was also achieved by knocking down WIPI-2, suggesting that both WIPI-1 and WIPI-2 are functionally required and not redundant in mediating the PI3P signal at the onset of autophagy in NB4 cells. In line with these data, downregulation of PI3KC3 (hVPS34), which generates PI3P upstream of WIPIs, also inhibited neutrophil differentiation. In conclusion, we demonstrate that both WIPI-1 and WIPI-2 are required for the PI3P-dependent autophagic activity during neutrophil differentiation, and that PU.1-dependent WIPI-1 expression is significantly repressed in primary AML patient samples and that the induction of autophagic flux is associated with neutrophil differentiation of APL cells.
5. Freeze-fracture replica immunolabelling reveals human WIPI-1 and WIPI-2 as membrane proteins of autophagosomes. Proikas-Cezanne T, et al. J Cell Mol Med, 2011 Sep. PMID 21564513, Free PMC Article

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GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. BAG1, CHMP2B, PEX3, and WIPI1 confirmed a strong differential gene expression, in 355 melanoma samples.
2. The specific autophagosomal localization of both WIPI1 and WIPI2 (refered to as WIPI puncta) has been employed to assess autophagy using fluorescence microscopy methods, such as confocal and live-cell video microscopy
3. Data suggest WIPI1/WIPI2 co-localize with microtubule-associated light chain 3 and autophagy related proteins 2/14L, participate in biogenesis of phagosomes, autophagy, and mobilization of lipids to/from intracellular droplets. [review-like article]
4. WIPI-1 and WIPI-2 are functionally required in mediating the PI3P signal at the onset of autophagy in NB4 cells.
5. the detection of WIPI1 mRNA is likely to be a convenient method of monitoring autophagosome formation in a wide range of cell types
6. Freeze-fracture replica immunolabelling reveals WD-repeat protein interacting with phosphoinositides 1 and 2 (WIPI-1 and WIPI-2) as membrane components of autophagosomes and the plasma membrane (PM).The notion that autophagosomal membranes are profoundly enriched in phosphatidylinositol 3‐phosphate (PtdIns(3)P) [8] is of key interest because autophagy is positively regulated by the activation of the phosphatidylinositol 3‐kinase class III complex 1, also including the tumour suppressor protein Beclin 1, that generates PtdIns(3)P [9]. Previously, we identified the human WIPI gene family that is aberrantly expressed in a variety of human cancer types [10]. We found that the WIPI protein family represents an ancient PtdIns(3)P/PtdIns(3,5)P₂‐binding β‐propeller protein family that includes WIPI‐1 and WIPI‐2 [10], both of which evolved from the yeast ancestral autophagy protein Atg18 [10, 11]. We characterized WIPI‐1 as a PtdIns(3)P‐effector protein functioning in the process of autophagy in human cancer cells [10, 12, 13]. Upon the induction of autophagy and the generation of PtdIns(3)P, both WIPI‐1 and WIPI‐2 specifically bind PtdIns(3)P and localize at initial autophagosomal membranes (phagophore) that are positive for further autophagy proteins, such as microtubule‐associated protein 1 light chain 3 (LC3) and Atg16 [10-14]. To clarify the precise localization of WIPI‐1 and WIPI‐2 upon the induction of autophagy we conducted freeze‐fracture immuno‐electron microscopy (immuno‐EM) because this method allows the employment of native, unfixed cells and, depending on the fracture, either of the two monolayers of a bilayer membrane is preserved [15].
   
7. Studies define a distinct role for WIPI1 and TORC1 signaling in controlling the transcription of melanogenic enzymes and melanosome maturation, a process that is distinct from starvation-induced autophagy.
8. Observational study and genome-wide association study of gene-disease association. (HuGE Navigator)
9. Quantification of WIPI-1 puncta should be suitable to assay mammalian autophagy
10. share an evolutionary conserved function in autophagy and that autophagic capacity may be compromised in human cancers

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IPK domeeni ja kromatiinin kypsyminen, IP6K2

 Sofistinen juttu histonien asteittaisesta kypsymisestä,  jossa on   myöhäinen deasetylaatiovaihe  histonien kypsymisessä ja siinä vaikuttaa olevan osuutta HDAC kaltaisesti toimivalla   IP6K2;n arginiinipitoisella   domeenilla. ( oma päätelmäni, mutta en löydä suoria  "valokuvia" asiasta) ihmiseltä.

https://www.ncbi.nlm.nih.gov/pubmed/31172592

J Cell Biochem. 2019 Jun 6. doi: 10.1002/jcb.29147. [Epub ahead of print]

Quercetin modifies 5'CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells.

Kedhari Sundaram M¹, Hussain A¹, Haque S², Raina R¹, Afroze N¹.

 Abstract
The central role of epigenomic alterations in carcinogenesis has been widely acknowledged, particularly the impact of DNA methylation on gene expression across all stages of carcinogenesis is considered vital for both diagnostic and therapeutic strategies. Dietary phytochemicals hold great promise as safe anticancer agents and effective epigenetic modulators. This study was designed to investigate the potential of a phytochemical, quercetin as a modulator of the epigenetic pathways for anticancer strategies. Biochemical activity of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and global genomic DNA methylation was quantitated by an enzyme-linked immunosorbent assay based assay in quercetin-treated HeLa cells. Molecular docking studies were performed to predict the interaction of quercetin with DNMTs and HDACs. Quantitative methylation array was used to assess quercetin-mediated alterations in the promoter methylation of selected tumor suppressor genes (TSGs). Quercetin induced modulation of chromatin modifiers including DNMTs, HDACs, histone acetyltransferases (HAT) and HMTs, and TSGs were assessed by quantitative reverse transcription PCR (qRT-PCR). It was found that quercetin modulates the expression of various chromatin modifiers and decreases the activity of DNMTs, HDACs, and HMTs in a dose-dependent manner. Molecular docking results suggest that quercetin could function as a competitive inhibitor by interacting with residues in the catalytic cavity of several DNMTs and HDACs. Quercetin downregulated global DNA methylation levels in a dose- and time-dependent manner. The tested TSGs showed steep dose-dependent decline in promoter methylation with the restoration of their expression. Our study provides an understanding of the quercetin's mechanism of action and will aid in its development as a candidate for epigenetic-based anticancer therapy.

A Class II Histone Deacetylase Acts on Newly Synthesized Histones in ...

https://ec.asm.org/content/7/3/471

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av JJ Smith - ‎2008 - ‎Citerat av 12 - ‎Relaterade artiklar

Most systems share the difficulty of separating chromatin maturation-related from ..... Thd2 is a class II HDAC with a putative IPK domain similar to Ipk2.

Kommentti: ...hiivan . (ArgRIII) ..ihmisellä IPKL domeeni, joka on arginiinipitoinen , IP6K2 entsyymin domeeni.

Front Oncol. 2019 May 22;9:432. doi: 10.3389/fonc.2019.00432. eCollection 2019. Intersection of Epigenetic and Metabolic Regulation of Histone Modifications in Acute Myeloid Leukemia.

Dhall A¹, Zee BM¹, Yan F², Blanco MA². Abstract

Acute myeloid leukemia (AML) is one of the most lethal blood cancers, accounting for close to a quarter of a million annual deaths worldwide. Even though genetically heterogeneous, all AMLs are characterized by two interrelated features-blocked differentiation and high proliferative capacity. Despite significant progress in our understanding of the molecular and genetic basis of AML, the treatment of AMLs with chemotherapeutic regimens has remained largely unchanged in the past 30 years. In this review, we will consider the role of two cellular processes, metabolism and epigenetics, in the development and progression of AML and highlight the studies that suggest an interconnection of therapeutic importance between the two. Large-scale whole-exome sequencing of AML patients has revealed the presence of mutations, translocations or duplications in several epigenetic effectors such as DNMT3, MLL, ASXL1, and TET2, often times co-occuring with mutations in metabolic enzymes such as IDH1 and IDH2. These mutations often result in impaired enzymatic activity which leads to an altered epigenetic landscape through dysregulation of chromatin modifications such as DNA methylation, histone acetylation and methylation. We will discuss the role of enzymes that are responsible for establishing these modifications, namely histone acetyl transferases (HAT), histone methyl transferases (HMT), demethylases (KDMs), and deacetylases (HDAC), and also highlight the merits and demerits of using inhibitors that target these enzymes. Furthermore, we will tie in the metabolic regulation of co-factors such as acetyl-CoA, SAM, and α-ketoglutarate that are utilized by these enzymes and examine the role of metabolic inhibitors as a treatment option for AML. In doing so, we hope to stimulate interest in this topic and help generate a rationale for the consideration of the combinatorial use of metabolic and epigenetic inhibitors for the treatment of AML.   KEYWORDS:

AML—acute myeloid leukaemia; HDACs; epigenetics (methylation/demethylation); histone methlyation; metabolism

Orgaanisen fosforin ja epäorgaanisten fosfaattien pitoisuudesta ravinnossa. Vaikutus seerumin fosfaattiin.

Am J Clin Nutr. 2015 Aug;102(2):444-53. doi: 10.3945/ajcn.114.102715. Epub 2015 Jun 3. Association of dietary phosphate and serum phosphorus concentration by levels of kidney function.

Moore LW¹, Nolte JV², Gaber AO², Suki WN³. Abstract BACKGROUND:

The health implications of dietary phosphorus intake and the role of kidney function in managing serum phosphorus homeostasis are well studied. However, examining the source of dietary phosphorus intake and its impact on serum phosphorus has not been characterized in population studies. OBJECTIVE:
This study aimed to distinguish the association of food sources of organic phosphorus and inorganic phosphate additives with serum phosphorus concentration.
 DESIGN:
A cross-sectional analysis of 24-h food recall data from 7895 adult participants in the National Health and Nutrition Examination Survey 2003-2006 was performed. Phosphorus content of foods was categorized as organic or inorganic. Correlations of serum phosphorus to clinical and dietary intake variables were achieved by using multiple regression analysis.
RESULTS:
After controlling for estimated glomerular filtration rate (eGFR), body mass index (BMI; in kg/m²), and albumin-to-creatinine ratio, a significant increase in serum phosphorus occurred with dairy foods with inorganic phosphates [parameter estimate (PE) ± SE: 0.07 ± 0.02 mg/dL, P < 0.01] or without inorganic phosphates (PE: 0.02 ± 0.01, P < 0.001) and cereals/grains with inorganic phosphates (PE: 0.005 ± 0.002, P < 0.01). Significantly higher serum phosphorus occurred when eGRF was <30 -0.09="" -0.10="" -0.11="" 0.0001="" 0.01="" 0.03="" 0.04="" 0.05="" 0.08="" 0.18="" 0.24="" 30-44="" 45-60="" and="" associated="" bmi="" but="" egfr="" higher="" lower="" or="" p="0.014). </p" phosphorus="" serum="" was="" were="" with="">CONCLUSIONS:
This analysis shows that dairy products and cereals/grains having inorganic phosphate additives significantly increase serum phosphorus concentration, despite being consumed less frequently than foods without phosphate additives. It seems prudent for the Nutrient Facts Label to include phosphorus but also for food manufacturers to consider alternatives to phosphate additives.
TRIAL REGISTRATION:
ClinicalTrials.gov NCT02435017.

© 2015 American Society for Nutrition.

KEYWORDS:
body mass index; chronic kidney disease; diet; dietary phosphorus; kidney disease

Comment in

• Studying dietary phosphorus intake: the challenge of when a gram is not a gram. [Am J Clin Nutr. 2015]
  
  J Ren Nutr. 2017 Mar;27(2):97-105. doi: 10.1053/j.jrn.2016.08.009. Epub 2016 Oct 14.
  
  Replacing Phosphorus-Containing Food Additives With Foods Without Additives Reduces Phosphatemia in End-Stage Renal Disease Patients: A Randomized Clinical Trial.
  de Fornasari ML¹, Dos Santos Sens YA².AbstractOBJECTIVE:
  The purpose of the study was to verify the effects of replacing phosphorus-containing food additives with foods without additives on phosphatemia in end-stage renal disease (ESRD) patients. DESIGN:
  Randomized clinical trial.SETTING:
  Adult patients on hemodialysis for ≥6 months at a single center. SUBJECTS:
  A total of 134 patients with phosphorus levels of >5.5 mg/dL were included and were randomized into an intervention group (n = 67) and a control group (n = 67). INTERVENTION:
  The IG received individual orientation to replace processed foods that have phosphorus additives with foods of similar nutritional value without these additives. The CG received only the nutritional orientation given before the study. Clinical laboratory data, nutritional status, energy and protein intake, and normalized protein nitrogen appearance (nPNA) were evaluated at the beginning of the study and after 90 days. RESULTS:
  There was no initial difference between the groups in terms of serum phosphorus levels, nutritional status, and energy intake. After 3 months, there was a decline in phosphorus levels in the IG (from 7.2 ± 1.4 to 5.0 ± 1.3 mg/dL, P < .001), but there was no significant difference in the CG (from 7.1 ± 1.2 to 6.7 ± 1.2 mg/dL, P = .65). In the IG, 69.7% of the patients reached the serum phosphorus target of ≤5.5 mg/dL; however, only 18.5% of the CG subjects reached this level (P < .001). CONCLUSION: At the end, there was no difference between the two groups in terms of nutritional status, energy intake, protein intake, and nPNA. The replacing phosphorus-containing food additives with foods without additives reduced serum phosphorus without interfering in the nutritional status of ESRD patients.
  

  Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.PMID: 27751628 DOI: 10.1053/j.jrn.2016.08.009
  
  
  
  Jos minulta kysyttäisiin, miten käytännössä voi tasapainotaa tätä orgaanista ja epäorgaanista  fosfaatinsaantiaan, sanoisin  neuvon jota itse noudatan kauta vuoden:  Vältän hiivalla leipomista. Harvoin ostan hiivalla leivottua leipää. Mielelläni käytän  hiilihydraattina  keitettyä riisiä, riisi- ja maissikeksiä , myslejä, tattaripuuroa,  kuivia hedelmiä , tuorehedelmiä, perunaa. Voin olla  itse koko vuoden käyttämättä hiivaa, mutta teen kyllä simaa vapuksi hiivalla.
  ... Hiiva nimittäin rikkoo fytiinin IP6  alemmiksi fosfaattimuodoiksi ja lopulta inositoliksi ja epäorgaaniseksi fosfaatiksi, jolloin  IP6:n antioksidanttista ja munuaisedullsita vaikutusta ei enää dieetistä  ole.
  Toinen tapa nostaa fytiinin saantia on nuo pähkinät , jyvät,  ym joita ei ole hiivalla hajoitettu.
  Fytiiniä on  monissa  kasviperäisissä ruoissa,  kaakaossakin.  ( Tässä blogissa on taulukkoja Spiller A Gene) .
  Samalla kun vältän hiivaa ja siitä tulevaa orgaanista  fosforia, koetan välttää myös bikarbonaattia, vaikka  sitä on vaikea välttää keliakiadieetissä, koska kaikki valmisjauhot  sisältävät natriumbikarbonaattia.  Jos tekee kakkuja tai torttuja, niihin  kyllä tulee bikarbonaattia, mutta  ei niitä tarvitse usein tehdä., juhliin vain.
  Valkoisen sokerin käytön koetan minimoida, sillä valkoinen sokeri kilpailee kovasti inositolin kanssa soluun pääsystä ja sokeri voittaa inositolin, varsinkin liikasokeri, joka lisäksi vähentää magnesiumpitoisuutta solusta.
  Kuitenkin näen aivan  mahdottomaksi  antaa tällaisia neuvoja, koska  esim  vehnäpulla ja kohotettu  leipä  on  perustava elintarvike   Pohjolassa.
  Minulla on tietysti  vahva motivaatio, joka auttaa pitämään  tällaista dieettiperiaatetta läpi vuoden:    verenpaine, joka  helposti nosuee ja  munuaistoiminta, joka vaikuttaa  vuosien varrella hieman   alamäkiseltä.  Joudun myös  pitämään  vähäsuolaista  dieettiä ruokasuolan suhteen ja  hyvin vahvasti  mineraalipitoista  kasvisperäisen  kaliumin ja magnesiumin suhteen, joita saan hedelmistä. Ei mistään tableteista kuitenkaan, koska niitä on  runsaasti tietyissä ravinteissa (mm.  kuivahedelmät, viikuna, taateli, luumu , pähkinät, mantelit) .
  
  
   

IP6K2 ja PPIP5K. Vaikutus solusykliin, p53:een ja bioenergeettisen tasapainoon

1. PPIP5K

KO of 5-InsP₇ kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype.

Gu C, Nguyen HN, Ganini D, Chen Z, Jessen HJ, Gu Z, Wang H, Shears SB.

Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):11968-11973. doi: 10.1073/pnas.1702370114. Epub 2017 Oct 25. Abstract

The inositol pyrophosphates 5-InsP₇ (diphosphoinositol pentakisphosphate) and 1,5-InsP₈ (bis-diphosphoinositol tetrakisphosphate) are highly energetic cellular signals interconverted by the diphosphoinositol pentakisphosphate kinases (PPIP5Ks). 
Here, we used CRISPR to KO PPIP5Ks in the HCT116 colon cancer cell line. This procedure eliminates 1,5-InsP₈ and raises 5-InsP₇ levels threefold. Expression of p53 and p21 was up-regulated; proliferation and G1/S cell-cycle transition slowed. Thus, PPIP5Ks are potential targets for tumor therapy. Deletion of the PPIP5Ks elevated [ATP] by 35%; both [ATP] and [5-InsP₇] were restored to WT levels by overexpression of PPIP5K1, and a kinase-compromised PPIP5K1 mutant had no effect. This covariance of [ATP] with [5-InsP₇] provides direct support for an energy-sensing attribute (i.e., 1 mM K_m for ATP) of the 5-InsP₇-generating inositol hexakisphosphate kinases (IP6Ks). We consolidate this conclusion by showing that 5-InsP₇ levels are elevated on direct delivery of ATP into HCT116 cells using liposomes. Elevated [ATP] in PPIP5K^-/- HCT116 cells is underpinned by increased mitochondrial oxidative phosphorylation and enhanced glycolysis. To distinguish between 1,5-InsP₈ and 5-InsP₇ as drivers of the hypermetabolic and p53-elevated phenotypes, we used IP6K2 RNAi and the pan-IP6K inhibitor, N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl) purine (TNP), to return 5-InsP₇ levels in PPIP5K^-/- cells to those of WT cells without rescuing 1,5-InsP₈ levels. Attenuation of IP6K restored p53 expression but did not affect the hypermetabolic phenotype. Thus, we conclude that 5-InsP₇ regulates p53 expression, whereas 1,5-InsP₈ regulates ATP levels. These findings attribute hitherto unsuspected functionality for 1,5-InsP₈ to bioenergetic homeostasis.

Published under the PNAS license.

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Select item 224469642.

Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles.

Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A, Ellis P, Langford C, Vannberg FO, Knight JC.

Nat Genet. 2012 Mar 25;44(5):502-10. doi: 10.1038/ng.2205.

-- Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 (znf) in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10(-15)), PRIC285 (P = 3.0 × 10(-10)) and an upstream region of CDKN1A (P = 2 × 10(-52)), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis.Free PMC Article

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Select item 210789643.

p53-mediated apoptosis requires inositol hexakisphosphate kinase-2.

Koldobskiy MA, Chakraborty A, Werner JK Jr, Snowman AM, Juluri KR, Vandiver MS, Kim S, Heletz S, Snyder SH.

Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20947-51. doi: 10.1073/pnas.1015671107. Epub 2010 Nov 15.

Inositol pyrophosphates (PP-InsPx)  have been implicated in numerous biological processes.

 Inositol hexakisphosphate kinase-2 (IP6K2), which generates the inositol pyrophosphate , PP-IP5, diphosphoinositol pentakisphosphate (IP7), influences apoptotic cell death. The tumor suppressor p53 responds to genotoxic stress by engaging a transcriptional program leading to cell-cycle arrest or apoptosis. 

We demonstrate that IP6K2 is required for p53-mediated apoptosis and modulates the outcome of the p53 response. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets such as the cyclin-dependent kinase inhibitor p21.Free PMC Article

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Select item 113374974.

Inositol hexakisphosphate (IP6)kinase 2 mediates growth suppressive and apoptotic effects of interferon-beta in ovarian carcinoma cells.

Morrison BH, Bauer JA, Kalvakolanu DV, Lindner DJ.

J Biol Chem. 2001 Jul 6;276(27):24965-70. Epub 2001 May 3. Abstract

Interferons (IFNs) regulate the expression of genes that mediate their antiviral, antitumor, and immunomodulatory actions. We have previously shown that IFN-beta suppresses growth of human ovarian carcinoma xenografts in vivo and induces apoptosis of ovarian carcinoma cells in vitro. To investigate mechanisms of IFN-beta-induced apoptosis we employed an antisense technical knockout approach to identify gene products that mediate cell death and have isolated several regulators of interferon-induced death (RIDs). In this investigation, we have characterized one of the RIDs, RID-2. Sequence analysis revealed that RID-2 was identical to human inositol hexakisphosphate kinase 2 (IP6K2). IP6K2 is post-transcriptionally induced by IFN-beta in ovarian carcinoma cells. A mutant IP6K2 with substitutions in the putative inositol phosphate binding domain abrogates IFN-beta-induced apoptosis. These studies identify a novel function for IP6K2 in cell growth regulation and apoptosis.

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 https://www.ncbi.nlm.nih.gov/pubmed/29512757