PDCD10 (Programmed cell death 10)

2016-08-01   Urfali-Mamatoglu , Hasan Huseyin Kazan , Ufuk Gunduz 

Department of Biological Sciences, Middle East Technical University, Ankara, Turkey. cagri.urfali@metu.edu.tr; hasanhuseyinkazan@gmail.com; ufukg@metu.edu.tr

Identity

HGNC
LOCATION
3q26.1
IMAGE
Atlas Image
LEGEND
Local order of PDCD10 is shown together with leading and subsequent genes on chromosome 3. The direction of arrows indicates transcriptional directions on the chromosome and arrow sizes approximate gene sizes.
LOCUSID
ALIAS
CCM3,TFAR15

Abstract

PDCD10 is a novel apoptosis regulator which functions in the regulation of cellular proliferation and apoptosis.

DNA/RNA

Atlas Image
Boxes are exons and the lines are introns.

Description

The PDCD10 gene is 51,688 bp in length, located on the minus strand and spans 9 exons (NCBI, 2016).

Transcription

3 different alternatively spliced mRNAs (1454, 1313 and 1212 bp long, respectively) that differ only in 5UTRs; 639 bp long open reading frame (NM_007217.3, NM_145859.1, NM_145860.1).

Pseudogene

LOC100128686 programmed cell death 10 pseudogene; located on 8q11.21 (NCBI, 2016).

Proteins

Description

PDCD10 encodes an evolutionarily conserved 212 amino acid long protein (Wang et al, 1999). PDCD10 has an estimated molecular weight of 29 kDa.

Expression

PDCD10 is expressed in all tissues including brain, pancreas, breast, ovary, kidney, liver and lungs (The Human Protein Atlas, 2016).

Localisation

PDCD10 is localized in cytoplasm, near Golgi apparatus and nucleus (Fidalgo et al, 2010).

Function

The PDCD10 protein regulates cell proliferation and transformation by modulating the extracellular signal-regulated kinase (ERK) pathway through interaction with serine/threonine protein kinase STK26 (MST4) (Ma et al, 2007). It also interacts with another serine/threonine kinase, STK25 , and triggers apoptosis under oxidative stress (Zhang et al, 2012). PDCD10 interacts with members of germinal center kinases III subfamily to promote normal Golgi assembly and cell orientation (Fidalgo, 2010). PDCD10 involves in the stabilization of KDR (VEGFR2) signaling and is vital for normal vascular development (He et al, 2010). PDCD10 acts downstream of gamma-protocadherins and regulate neuronal survival (Lin et al, 2010).

Mutations

Germinal

Cerebral cavernous malformations are associated with the mutations in 3 loci; one of which is CCM3/PDCD10. Bergametti et al reported a de novo deletion as well as six other deleterious mutations in PDCD10 gene. Three of these mutations were stated as nonsense mutations, two other mutations were reported to generate aberrant splicing in exon 9 with a frameshift and the last one caused an abnormal splicing in exon 5 without frameshift (Bergametti et al, 2005). In a study with 61 families with cerebral caverous malformations, Guclu et al (2005) identified two identical mutations creating a premature stop codon in exon 7, two frameshift mutations in exon 6 and one additional frameshift mutation in exon 9 (Guclu et al, 2005). In patients without KRIT1 (CCM1) and CCM2 mutations, Verlaan et al (2005) identified two mutations in CCM3 which lead to a truncated PDCD10 protein. One of the mutations was a nonsense mutation in exon 7 caused by a transversion o a C to a T that creates a stop codon and the other one was reported to be an invariant splice acceptor site mutation (Verlaan et al, 2005). Riant et al (2013) reported that, in 13 of 54 CCM3-mutated patients, there are deletions in one or several coding exons; 8 of which deletions are whole gene deletions. In 41 patients, several point mutations leading abnormal splicing, nonsense mutations and small insertions and deletions causing frameshifts and premature stop codons were identified. Additionally, they reported deletions in noncoding exons 1-3 in a 5-year old child with cerebral carcinomas (Riant et al, 3013).

Implicated in

Entity name
Cerebral cavernous malformations
Disease
Cerebral cavernous malformations (CCM) is one of the frequently occurring cerebral vascular abnormalities characterized by abnormally enlarged blood vessels that cause brain hemorrhages and seizures which result in focal neurological deficits (Rigamonti et al, 1998; Bergametti et al, 2005). Bergametti et al identified PDCD10 as the CCM3 gene and reported several mutations in this locus (Bergametti et al, 2005). Several other studies also reported different mutations in PDCD10 gene in patients with cerebral cavernous malformations and cerebral carcinomas (see Mutations section above).
Entity name
Prostate cancer
Note
PDCD10 is expressed in both benign prostatic hyperplasia and prostate cancer with a stronger staining in prostate cancer cases. Germinal center kinases, MST4 and STK25, are also significantly overexpressed in prostate cancer and associated with the PDCD10 expression (Zhang et al, 2014). miR-103 is reported to regulate PDCD10 in prostate cancer and when overexpressed, it suppresses tumor cell proliferation by targeting PDCD10 (Fu et al, 2016).
Entity name
Note
PDCD10 is constitutiely expressed in malignant T cells and cell lines derived from peripheral blood of patients with Sezary syndrome (T cell lymphoma). PDCD10 is found to be constitutively associated with protein phosphatase-2A (PP2A) which is essential in the regulation of cell proliferation and apoptosis in T cell lymphoma. Depletion of PDCD10 was reported to significantly increase apoptosis in various malignant T cells (Lauenborg et al, 2010).
Entity name
Colorectal cancer
Note
Zhang et al (2016) reported that PDCD10 expression was down-regulated in drug-resistant colorectal cancer cells. The expression of PDCD10 was regulated by MIR425 (mature sequence miR-425-5p) which directly targets 3-UTR of PDCD10 (Zhang et al, 2016).

Bibliography

Pubmed IDLast YearTitleAuthors
155434912005Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations.Bergametti F et al
203321132010CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation.Fidalgo M et al
267717622016MicroRNA-103 suppresses tumor cell proliferation by targeting PDCD10 in prostate cancer.Fu X et al
162845702005Mutations in apoptosis-related gene, PDCD10, cause cerebral cavernous malformation 3.Guclu B et al
203717692010Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development.He Y et al
208544652010Programmed cell death-10 enhances proliferation and protects malignant T cells from apoptosis.Lauenborg B et al
173609712007PDCD10 interacts with Ste20-related kinase MST4 to promote cell growth and transformation via modulation of the ERK pathway.Ma X et al
238019322013CCM3 Mutations Are Associated with Early-Onset Cerebral Hemorrhage and Multiple Meningiomas.Riant F et al
163806262005CCM3 mutations are uncommon in cerebral cavernous malformations.Verlaan DJ et al
202293481999cDNA cloning and expression of an apoptosis-related gene, humanTFAR15 gene.Wang Y et al
226527802012PDCD10 interacts with STK25 to accelerate cell apoptosis under oxidative stress.Zhang H et al

Other Information

Locus ID:

NCBI: 11235
MIM: 609118
HGNC: 8761
Ensembl: ENSG00000114209

Variants:

dbSNP: 11235
ClinVar: 11235
TCGA: ENSG00000114209
COSMIC: PDCD10

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000114209ENST00000392750Q9BUL8
ENSG00000114209ENST00000461494Q9BUL8
ENSG00000114209ENST00000462725C9JND6
ENSG00000114209ENST00000464360C9J932
ENSG00000114209ENST00000470131Q9BUL8
ENSG00000114209ENST00000471885C9J6F3
ENSG00000114209ENST00000473645Q9BUL8
ENSG00000114209ENST00000475915C9J5C3
ENSG00000114209ENST00000479121H7C5M9
ENSG00000114209ENST00000487947C9J6F3
ENSG00000114209ENST00000492139C9JSA3
ENSG00000114209ENST00000492396C9J363
ENSG00000114209ENST00000494502F8WDF3
ENSG00000114209ENST00000497056Q9BUL8

Expression (GTEx)

0
10
20
30
40
50
60
70

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
155434912005Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations.116
190881232009Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.83
190881242009A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.69
176575162007CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations.68
205924722010CCM3 signaling through sterile 20-like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations.65
173609712007PDCD10 interacts with Ste20-related kinase MST4 to promote cell growth and transformation via modulation of the ERK pathway.60
203321132010CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation.50
251221442015Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.46
183002722008Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex.40
162845702005Mutations in apoptosis-related gene, PDCD10, cause cerebral cavernous malformation 3.38

Citation

Urfali-Mamatoglu ; Hasan Huseyin Kazan ; Ufuk Gunduz

PDCD10 (Programmed cell death 10)

Atlas Genet Cytogenet Oncol Haematol. 2016-08-01

Online version: http://atlasgeneticsoncology.org/gene/43399/pdcd10