Ser/Thr protein phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest

Ligand-induced glucocorticoid receptor (GR) activation has recently been li nked to the inhibition of cell proliferation via the transcriptional induct ion of p21(WAF1/Cip1), which functions as a universal inhibitor of cyclin-d ependent protein kinases. Herein, we identify a Ser/Thr protein phosphatase (PP5) that promotes cellular proliferation by inhibiting both glucocortico id and p53-mediated signaling pathways leading to p21(WAF1/Cip1)-mediated g rowth arrest. The suppression of PP5 expression (1) markedly increases the association of GR with its cognate DNA-binding sequence, (2) induces GR tra nscriptional activity without the addition of hormone, and (3) increases de xamethasone-mediated induction of GR reporter activity to a level that is s imilar to 10 times greater than the maximal response obtainable in the pres ence of PP5. PP5 has no apparent effect on the binding of hormone to the GR , and dexamethasone-mediated growth arrest correlates with an increase in p 53 phosphorylation. Comparative studies in p53-wild-type, p53-defective, an d p53-deficient cell lines indicate that either (1) p53 participates in GR- mediated induction of p21(WAF1/Cip1), with the hyperphosphorylation of basa l p53 induced by glucocorticoids sufficient for the propagation of an antip roliferative response when PP5 expression is inhibited, or (2) PP5 acts whe re p53-mediated and GR-induced signaling networks converge to regulate the transcriptional induction of p21(WAF1/Cip1). Thus, aberrant PP5 expression may have an additive effect on the development of human cancers by promotin g cell proliferation via the inhibition of a GR-induced antiproliferative s ignaling cascade, and facilitating neoplastic transformation via the inhibi tion of a growth-arresting p53-mediated response that guards against genomi c instability.