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Mutant p53: Epigenetic mutator of the T‐cell receptor via induction of methylation
Author(s) -
Iwamoto Keisuke S.,
Mizuno Terumi,
Seyama Toshio,
Kyoizumi Seishi
Publication year - 1999
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/(sici)1098-2744(199906)25:2<113::aid-mc6>3.0.co;2-d
Subject(s) - biology , t cell receptor , carcinogenesis , epigenetics , dna methylation , jurkat cells , cancer research , gene silencing , t cell , microbiology and biotechnology , genetics , gene , gene expression , immune system
The mechanism and effects of epigenetic alterations in human carcinogenesis are not well understood, except that cancers often have alterations in the methylation status of their genomes. Additionally, human cancers, including aggressive T‐cell leukemias and lymphomas, have a high frequency of p53 mutations, particularly missense mutations, which raises the possibility of gain‐of‐new‐function proteins, but the new proteins' oncogenic functions are mechanistically ill‐defined. To investigate the mechanisms behind the high prevalence of p53 tumor suppressor gene mutations in aggressive or relapsed T‐cell leukemias, we transfected Jurkat cells null for p53 protein with a temperature‐sensitive p53 mutant. We showed that this mutant p53 abrogated expression of the T‐cell antigen receptor (TCR) by affecting the methylation of an at least 20‐kb region of DNA, 5′; to the TCR β‐chain gene enhancer region, which includes TCRβC1 and βC2 . Expression of the TCR is restored when the temperature is reduced to 32°C, at which temperature the mutant p53 regains wild‐type function. The TCR, a common site of dysfunction in T‐cell malignancies, is the principal signal transduction moiety controlling both T‐cell activation and activation‐induced apoptosis. These results suggest a new role for mutant p53—as an epigenetic mutator, bridging p53, methylation, and transcriptional silencing—and suggest novel mechanisms in immunosuppression and cancer progression. Mol. Carcinog. 25:113–121, 1999. © 1999 Wiley‐Liss, Inc.