Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5'-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.
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PMID:Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5. 2816 33

Mutations in cancer abolish normal tumor suppressive functions of tumor protein p53 (TP53, best known as p53) and convert it into an oncogene. We recently reported the identification of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a transcriptional target of mutant p53 that enhances folding of N-glycosylated proteins required for cancer cell migration, invasion, and metastasis.
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PMID:p53 gain-of-function mutations promote metastasis via ENTPD5 upregulation and enhanced N-glycoprotein folding. 2840 Nov 89