p73 and p63 Sustain Cellular Growth by Transcriptional Activation of Cell Cycle Progression Genes

Abstract

Despite extensive studies on the role of tumor suppressor p53 protein and its homologues, p73 and p63, following their overexpression or cellular stress, very little is known about the regulation of the three proteins in cells during physiologic cell cycle progression. We report a role for p73 and p63 in supporting cellular proliferation through the transcriptional activation of the genes involved in G 1 -S and G 2 -M progression. We found that in MCF-7 cells, p73 and p63, but not p53, are modulated during the cell cycle with a peak in S phase, and their silencing determines a significant suppression of proliferation compared with the control. Chromatin immunoprecipitation analysis shows that in cycling cells, p73 and p63 are bound to the p53-responsive elements (RE) present in the regulatory region of cell cycle progression genes. On the contrary, when the cells are arrested in G 0 -G 1 , p73 detaches from the REs and it is replaced by p53, which represses the expression of these genes. When the cells move in S phase, p73 is recruited again and p53 is displaced or is weakly bound to the REs. These data open new possibilities for understanding the involvement of p73 and p63 in cancer. The elevated concentrations of p73 and p63 found in many cancers could cause the aberrant activation of cell growth progression genes and therefore contribute to cancer initiation or progression under certain conditions.

p63 maintains keratinocyte proliferative capacity through regulation of Skp2–p130 levels

“…Taken together, we identify SKP2 as a novel proproliferative p63 target gene that probably exerts its function through targeted degradation of p130 and p21 to maintain cell proliferation (Bhattacharya et al, 2003;Yu et al, 1998). Supporting our findings, recent data indicate a positive role for p63 in maintaining expression of pro-proliferative cell cycle target genes and opposing p53-mediated repression (Lefkimmiatis et al, 2009).…”

Glutamine depletion and glucose depletion trigger growth inhibition via distinctive gene expression reprogramming

“…40 The activation of TP73 and HIC, 41,42 which encode two tumor suppressors, might attenuate the cell proliferation rate to match the decreased Gln availability, thus contributing to the slow-growing phenotype.…”

TAp73 Induction by Nitric Oxide

“…Both TAp73␣ and TAp73␤ can induce apoptosis in different cellular models and experimental conditions (14,27). Contrasting with these converging data, a few studies highlighted antiapoptotic or growth-promoting functions of TAp73␣ or TAp73␤ (52)(53)(54). It is interesting to note that the pro-or antiapoptotic activity of TAp73␣ is dependent on the cell type (52).…”