Diphthamide Biosynthesis Protein 2, S. Cerevisiae, Homolog-like 1 OKDB#: 2025
 Symbols: DPH2L1 Species: human
 Synonyms: OVARIAN CANCER-ASSOCIATED GENE 1, OVCA1  Locus: 17p13.3 in Homo sapiens


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General Comment A region of chromosome 17p13.3 bounded by loci D17S28 and D17S30 is deleted in 80% of all ovarian epithelial malignancies. By exon trapping, Phillips et al. (1996) isolated a cDNA from the common region of deletion. The predicted 363-amino acid protein was designated DPH2L (DPH2-like) because it shares 20% amino acid identity with the S. cerevisiae DPH2 (diphthamide biosynthesis-2) gene.
General function
Comment
Cellular localization Cytoplasmic
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Ovarian function
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Expression regulated by
Comment Polycystic ovary syndrome (PCOS) affects 5% of reproductive aged women and is the leading cause of anovulatory infertility. A hallmark of PCOS is excessive theca cell androgen secretion, which is directly linked to the symptoms of PCOS. Our previous studies demonstrated that theca cells from PCOS ovaries maintained in long term culture persistently secrete significantly greater amounts of androgens than normal theca cells, suggesting an intrinsic abnormality. Furthermore, previous studies suggested that ovarian hyperandrogenemia is inherited as an autosomal dominant trait. However, the genes responsible for ovarian hyperandrogenemia of PCOS have not been identified. In this present study, Wood JR, et al carried out microarray analysis to define the gene networks involved in excess androgen synthesis by the PCOS theca cells in order to identify candidate PCOS genes. Analysis revealed that PCOS theca cells have a gene expression profile that is distinct from normal theca cells. Included in the cohort of genes with increased mRNA abundance in PCOS theca cells were aldehyde dehydrogenase 6 and retinol dehydrogenase 2, which play a role in all-trans-retinoic acid biosynthesis and the transcription factor GATA6. We demonstrated that retinoic acid and GATA6 increased the expression of 17alpha-hydroxylase, providing a functional link between altered gene expression and intrinsic abnormalities in PCOS theca cells. Thus, the analyses have 1) defined a stable molecular phenotype of PCOS theca cells, 2) suggested new mechanisms for excess androgen synthesis by PCOS theca cells, and 3) identified new candidate genes that may be involved in the genetic etiology of PCOS. This is one of the genes with Altered mRNA Abundance in PCOS Theca Cells as compared with normal theca cells Maintained Under Basal Conditions.
Ovarian localization Theca
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Follicle stages
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Phenotypes
Mutations

Species: mouse -
type: null mutation
fertility: embryonic lethal
Comment: Loss of OVCA1/DPH2L1 correlates with ovarian and breast cancer. To study its in vivo role, Chen generated Ovca1 mutant alleles in mice. Ovca1 heterozygotes spontaneously develop cancer. Ovca1 mutant mice die during embryonic development and at birth with developmental delay and defects in multiple organ systems. Cell proliferation defects were observed in Ovca1 mutant mouse embryonic fibroblasts (MEFs). p53 deficiency can rescue these Ovca1 mutant MEF proliferation defects and partially rescue Ovca1 mutant embryonic phenotypes. Furthermore, Ovca1; p53 double heterozygotes developed tumors quicker than p53 heterozygotes and with an increased carcinoma incidence. Multiple tumor burden in Ovca1 heterozygotes that were also p53 deficient was significantly higher than in p53 homozygous mutants. These in vivo findings demonstrate that Ovca1 is a tumor suppressor that can modify p53-induced tumorigenesis and suggest that it acts as a positive regulator for cell cycle progression. The close linkage of OVCA1 and p53 on human Chromosome 17 suggests that coordinated loss may be an important mechanism for the evolution of ovarian, breast, and other tumor phenotypes.

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created: 2003-07-22 17:09:37 by: Rami  Rauch, hsuehlab   email: rrauch@stanford.edu
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