Helping p53 Choose a Target Gene

Abstract

The tumor suppressor p53 controls the cellular response to genotoxic stress by promoting either cell cycle arrest or apoptosis, depending on the amount of damage (see Aylon and Oren for summary of p53 functions and regulatory mechanisms). Much of the function of p53 in this cell choice of life or death is related to which genes it targets: Do those genes encode proapoptotic proteins or are encoded proteins involved in mediating cell cycle arrest? Two articles this week identify two new participants in controlling p53 target gene selection. Das et al . identified hematopoietic zinc finger (Hzf), which is itself encoded by a p53-regulated gene, as a protein that directly interacted with p53 and promoted the activation of cell cycle arrest genes, while inhibiting the expression of proapoptotic genes, in response to mild DNA damage. This function was determined using RNA interference assays and mouse embryo fibroblasts deficient in Hzf. Initially, in response to mild genotoxic stress, Hzf abundance increased; however, after prolonged exposure of cells to etopside or extended forced expression of p53, Hzf abundance decreased, which was prevented by pharmacological inhibition of the proteasome. This decrease correlated with the time in which the cells begin to undergo apoptosis; thus, Hzf appears to be one p53 target and partner that contributes to the choice of cell cycle arrest. In a related article, Tanaka et al . found that human cellular apoptosis susceptibility protein (hCAS, which is the homolog of the yeast protein CSE1) bound to a subset of p53-containing chromatin complexes, although binding of hCAS and p53 were independent of each other. When hCAS was depleted by RNA interference methods, the p53 target genes with which hCAS was normally associated showed decreased p53-dependent expression. Although hCAS-targeted genes did not fall exclusively into the cell cycle or apoptosis categories, hCAS does appear to be another mechanism by which p53 target gene selection is made. Y. Aylon, M. Oren, Living with p52, Dying of p53. Cell 130 , 597-600 (2007). [PubMed] S. Das, L. Raj, B. Zhao, Y. Kimura, A. Bernstein, S. A. Aaronson, S. W. Lee, Hzf determines cell survival upon genotoxic stress by modulating p53 transactivation. Cell 130 , 624-637 (2007). [PubMed] T. Tanaka, S. Ohkubo, I. Tatsuno, C. Prives, hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes. Cell 130 , 638-650 (2007). [PubMed]