Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bladder cancer is a common disease characterized by multiple recurrences and an invasive disease course in more than 10% of patients. It is of monoclonal or oligoclonal origin and genomic instability has been shown at certain loci. We used a 10,000 single nucleotide polymorphism (SNP) array with an average of 2,700 heterozygous SNPs to detect allelic imbalances (AI) in 37 microdissected bladder tumors from 17 patients. Eight tumors represented upstaging from Ta to T1, eight from T1 to T2+, and one from Ta to T2+. The AI was strongly stage-dependent as four chromosomal arms showed AI in > 50% of Ta samples, eight in T1, and twenty-two in T2+ samples. The tumors showed stage-dependent clonality as 61.3% of AIs were reconfirmed in later T1 tumors and 84.4% in muscle-invasive tumors. Novel unstable chromosomal areas were identified at chromosomes 6q, 10p, 16q, 20p, 20q, and 22q. The tumors separated into two distinct groups, highly stable tumors (all Ta tumors) and unstable tumors (2/3 muscle-invasive). All 11 unstable tumors had lost chromosome 17p areas and 90% chromosome 8 areas affecting Netrin-1/UNC5D/MAP2K4 genes as well as others. AI was present at the TP53 locus in 10 out of 11 unstable tumors, whereas 6 had homozygous TP53 mutations. Tumor distribution pattern reflected AI as seven out of eight patients with additional upper urinary tract tumors had genomic stable bladder tumors (P < 0.05). These data show the power of high-resolution SNP arrays for defining clinically relevant AIs.
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PMID:High-density single nucleotide polymorphism array defines novel stage and location-dependent allelic imbalances in human bladder tumors. 1566 77

UNC5H4 is a netrin-1 receptor UNC5H family member. In this study, we found that UNC5H4 is a direct transcriptional target of p53. During adriamycin (ADR)-mediated apoptosis, UNC5H4 was significantly induced in p53-proficient U2OS cells but not in p53-deficient H1299 cells. Enforced expression of p53 induced UNC5H4. Consistent with these results, siRNA-mediated knockdown of p53 in U2OS cells attenuated ADR-dependent induction of UNC5H4. Indeed, we found four putative p53-responsive elements within intron 1 of UNC5H4 gene. Luciferase reporter assay and ChIP analysis demonstrated that, among them, two tandem elements respond to exogenous p53 which is efficiently recruited onto them. Furthermore, enforced expression of UNC5H4 remarkably reduced number of drug-resistant colonies in p53-proficient cells but not in p53-deficient cells, suggesting that UNC5H4-induced apoptosis is dependent on p53 status. siRNA-mediated knockdown of UNC5H4 rendered U2OS cells resistant to ADR. Collectively, our present results suggest that UNC5H4 amplifies p53-dependent apoptotic response.
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PMID:A newly identified dependence receptor UNC5H4 is induced during DNA damage-mediated apoptosis and transcriptional target of tumor suppressor p53. 1840 67

Spontaneous regression of neuroblastoma (NB) resembles the developmentally regulated programmed cell death (PCD) of sympathetic neurons. Regressing tumor cells express high levels of the nerve growth factor (NGF) receptors TRKA and p75NTR and are dependent on NGF for survival; however, the underlying molecular mechanism remains elusive. Here, we show that UNC5D, a dependence receptor that is directly targeted by p53 family members, is highly expressed in favorable NBs. NGF withdrawal strongly upregulated UNC5D, E2F1, and p53 in human primary favorable NBs. The induced UNC5D was cleaved by caspases 2/3, and the released intracellular fragment translocated into the nucleus and interacted with E2F1 to selectively transactivate the proapoptotic target gene. The cleavage of UNC5D and its induction of apoptosis were strongly inhibited by addition of netrin-1. Unc5d(-/-) mice consistently exhibited a significant increase in dorsal root ganglia neurons and resistance to NGF depletion-induced apoptosis in sympathetic neurons compared with wild-type cells. Our data suggest that UNC5D forms a positive feedback loop with p53 and E2F1 to promote NGF dependence-mediated PCD during NB regression.
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PMID:Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression. 2377 38