Tumor Suppressors

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Science's STKE  02 Mar 2004:
Vol. 2004, Issue 222, pp. tw79-TW79
DOI: 10.1126/stke.2222004TW79

The tumor suppressor p53, a transcription factor activated in response to various stresses, promotes apoptosis and cell cycle arrest. PML, the protein product of the promyelocytic leukemia gene (PML), also acts as a tumor suppressor and is believed to act upstream of p53 to regulate its activity. De Stanchina et al. investigated the role of PML in cellular senescence and discovered that PML functioned as a direct p53 target. The authors used Western analysis to show that, in mouse embryo fibroblasts, the expression of p53 and PML was stimulated by oncogenic Ras. Stimulation of PML expression by Ras or in response to DNA damage depended on the presence of p53, and transfer of p53 into mouse and human cells lacking p53 increased the expression of PML mRNA and protein. Regions of the PML gene that contained putative p53 response elements (REs) enabled p53 to activate a heterologous gene reporter. Mutational analysis indicated that this sensitivity depended on REs. Moreover, electrophoretic mobility-shift analysis indicated that p53 bound to PML REs in vitro, and chromatin immunoprecipitation analysis indicated that p53 bound to the PML gene of cells expressing oncogenic Ras. Cells in which PML was suppressed (with short-hairpin RNA) showed specific defects in p53-mediated cell cycle arrest, senescence, and apoptosis (but not in some other p53 effects). Thus, PML appears to function as a direct target and an effector of p53. The authors discuss scenarios in which these data can be reconciled with previous research suggesting that PML acts upstream of p53.

E. de Stanchina, E. Querido, M. Narita, R. V. Davuluri, P. P. Pandolfi, G. Ferbeyre, S. W. Lowe, PML is a direct p53 target that modulates p53 effector functions. Mol. Cell 13, 523-535 (2004). [Online Journal]