Genome-wide studies of the transcriptional regulation by p53

Abstract

The tumor suppressor p53 is arguably the most important transcription factor that safeguards the genome. Although it is clear that the transcriptional activity of p53 is required for its tumor suppressive function, the underlying mechanisms are still largely unknown. In the past several years, genome-wide approaches have provided novel insights into the tumor suppressive functions of p53. This mini-review summarizes recent progress in studying these functions using genome-wide approaches, and offers some perspectives on this rapidly expanding field.

Rap2b, a novel p53 target, regulates p53-mediated pro-survival function

“…The list of p53 target genes is still expanding. 23,24 Thus far, there is no single p53 target that fully phenocopies p53, suggesting that p53 targets either cooperate to prevent tumors, or that we have not found the right downstream target. Therefore, identification of new p53 targets and investigation of their functions during p53 signaling is of paramount importance.…”

“…This result supports a model that p53-repressed genes are more likely to mediate the cell type-specific function of p53 than do the activated genes. 23,25 The mechanisms underlying the transcriptional repression by p53 are more complex than those for activation. 24,50 p53 can directly repress gene transcription by recruiting co-repressor, such as Sin3a and LSD1, or interfere with the enhancer activity.…”

“…6,7,23,24 Previous genomewide studies by us as well as others have identified a large number of p53 downstream targets. [25][26][27][28] Most of these studies have used a single cell type, and the comparisons between cell types have not been fully performed.…”

Yes-associated protein (YAP) increases chemosensitivity of hepatocellular carcinoma cells by modulation of p53

“…Initially, we assumed that p53 was also a transcription factor, 22,23 which could positively feedback YAP expression. To prove this assumption, HepG2 cells were transfected with empty vector or p53-overexpression vector, treated with doxorubicin for 24 h and then RNAs and proteins harvested for testing.…”

Mechanisms of p53 Functional De-Regulation: Role of the IκB-α/p53 Complex

“…While the role of p53 in cancer has mostly been associated with the genetic inactivation of TP53 through mutations and deletions [1,10], various novel p53 functions and targets have been discovered, with impressive consequences in tumorigenesis [1,11,12] and cancer therapy [13,14,15,16]. Indeed, the role of p53 in cancer should include the following, novel, non-canonical functions: (i) various TP53 mutations behave as gain of functions [1,17,18,19,20]; (ii) the p53 protein is no longer just a transcriptional factor [21,22,23,24], but acts in different cellular compartments outside the nucleus, where it mediates several processes through a complex network of partners [25,26,27,28]; (iii) wild-type p53 should also result in being functionally inactive through changes in compartmentalization or protein modifications [29,30,31]; and (iv) non-cell-autonomous tumor suppression properties of p53 have also been discovered [32]. All together, these intriguing p53 functions suggest that the role of p53 in cancer is much more complex and may be exploited from a therapeutic standpoint [15,33,34].…”