G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv

Abstract

In response to DNA damage, p53 activates a G1 cell cycle checkpoint, in part through induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Here we report the identification of a new direct p53 target, Ptprv (or ESP), encoding a transmembrane tyrosine phosphatase. Ptprv transcription is dramatically and preferentially increased in cultured cells undergoing p53-dependent cell cycle arrest, but not in cells undergoing p53-mediated apoptosis. This observation was further confirmed in vivo using a Ptprv null-reporter mouse line. A p53-responsive element is present in the Ptprv promoter and p53 is recruited to this site in vivo. Importantly, while p53-dependent apoptosis is intact in mice lacking Ptprv, Ptprv-null fibroblasts and epithelial cells of the small intestine are defective in G1 checkpoint control. Thus, Ptprv is a new direct p53 target and a key mediator of p53-induced cell cycle arrest. Finally, Ptprv loss enhances the formation of epidermal papillomas after exposure to chemical carcinogens, suggesting that Ptprv acts to suppress tumor formation in vivo.

Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death

“…Cell cycle arrest is mediated by transcriptional induction of genes whose products inhibit cell cycle progression, such as p21 Waf1/Cip11 or Ptprv. 2 The apoptotic function of p53 depends on both transcription-dependent and transcription-independent mechanisms. 3 The importance of p53 in tumor suppression is highlighted by the observation that virtually all human cancers display an impaired p53 response.…”

MDMX: from bench to bedside

“…These drive a variety of cellular responses to stress, including DNA repair, cell-cycle arrest, senescence and apoptosis. Key targets are the proapoptotic genes Bax, Puma and Noxa (Michalak et al, 2005), the genes encoding the cell cycle regulators p21 (el-Deiry et al, 1993) and Ptprv (Doumont et al, 2005) and the senescence-inducing gene Plasminogen activator inhibitor 1 (Kortlever et al, 2006).…”

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

“…Key mediators of p53 biological activities are the proapoptotic genes bax, PUMA and NOXA 2 and the cell cycle regulators p21 3 and Ptprv. 4 In the absence of stress signals, the p53 protein is kept in check to allow normal cell proliferation and/or maintenance of cell viability. Of critical importance for this process are the two structurally related proteins, Mdm2 and Mdm4 (also known as Mdmx).…”