Mutant p53: epigenetic mutator of the T-cell receptor via induction of methylation.
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 beta-chain gene enhancer region, which includes TCRbetaC1 and betaC2. Expression of the TCR is restored when the temperature is reduced to 32 degrees 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.
Iwamoto
K S
KS
Department of Radiobiology, Radiation Effects Research Foundation, Hiroshima, Japan.
Mizuno
T
T
Seyama
T
T
Kyoizumi
S
S
D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D005434:Flow Cytometry; D016158:Genes, p53; D006801:Humans; D019169:Jurkat Cells; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
D011948:Receptors, Antigen, T-Cell; D015254:DNA Modification Methylases