p73 and p63 sustain cellular growth by transcriptional activation of cell cycle progression genes.

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.

[1]  H. Ng,et al.  p73 supports cellular growth through c-Jun-dependent AP-1 transactivation , 2007, Nature Cell Biology.

[2]  Graziano Pesole,et al.  p53FamTaG: a database resource of human p53, p63 and p73 direct target genes combining in silico prediction and microarray data , 2007, BMC Bioinformatics.

[3]  D. Lane,et al.  p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress , 2006, Cell Death and Differentiation.

[4]  C. Saccone,et al.  The Fatty Acid Synthase Gene is a Conserved p53 Family Target Gene from Worm to Human , 2006, Cell cycle.

[5]  J. Manfredi,et al.  The Dual Specificity Phosphatase Cdc25C is a Direct Target for Transcriptional Repression by the Tumor Suppressor p53 , 2006, Cell cycle.

[6]  R. Mantovani,et al.  Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63 , 2006, Nucleic acids research.

[7]  Anna Maria D'Erchia,et al.  Connecting p63 to Cellular Proliferation: The Example of the Adenosine Deaminase Target Gene , 2006, Cell cycle.

[8]  A. Morgunkova.  The p53 Gene Family: Control of Cell Proliferation and Developmental Programs , 2005, Biochemistry (Moscow).

[9]  G. Blandino,et al.  A Role of p73 in Mitotic Exit* , 2005, Journal of Biological Chemistry.

[10]  Xin Lu,et al.  Cell cycle‐dependent nuclear retention of p53 by E2F1 requires phosphorylation of p53 at Ser315 , 2005, The EMBO journal.

[11]  J. Manfredi,et al.  DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter. , 2004, Molecular cell.

[12]  G. Matlashewski,et al.  Regulation of Human p53 Activity and Cell Localization by Alternative Splicing , 2004, Molecular and Cellular Biology.

[13]  U. Moll,et al.  p63 and p73: roles in development and tumor formation. , 2004, Molecular cancer research : MCR.

[14]  Stephen Dalton,et al.  Cdk6–cyclin D3 activity in murine ES cells is resistant to inhibition by p16INK4a , 2004, Oncogene.

[15]  G. Blandino,et al.  p73 Is Regulated by Phosphorylation at the G2/M Transition* , 2003, Journal of Biological Chemistry.

[16]  C. Saccone,et al.  Adenosine deaminase, a key enzyme in DNA precursors control, is a new p73 target , 2003, Oncogene.

[17]  Yoichi Taya,et al.  Cyclin-dependent Kinases Phosphorylate p73 at Threonine 86 in a Cell Cycle-dependent Manner and Negatively Regulate p73* , 2003, Journal of Biological Chemistry.

[18]  I. Screpanti,et al.  Differential regulation of E2F1 apoptotic target genes in response to DNA damage , 2003, Nature Cell Biology.

[19]  P. Hainaut,et al.  ΔN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53 , 2002, Oncogene.

[20]  W. Kaelin,et al.  Role of the newer p53 family proteins in malignancy , 2001, Apoptosis.

[21]  M. Y. Lee,et al.  Characterization of the 5'-flanking region of the gene encoding the 50 kDa subunit of human DNA polymerase delta. , 2000, Biochimica et biophysica acta.

[22]  P. Russell,et al.  The cdc25 M-phase inducer: An unconventional protein phosphatase , 1992, Cell.

[23]  D. Beach,et al.  Activation of cdc2 protein kinase during mitosis in human cells: Cell cycle-dependent phosphorylation and subunit rearrangement , 1988, Cell.