| Abstract
| - Ligand-induced glucocorticoid receptor (GR) activation has recently been linked to the inhibitionof cell proliferation via the transcriptional induction of p21WAF1/Cip1, which functions as a universal inhibitorof cyclin-dependent protein kinases. Herein, we identify a Ser/Thr protein phosphatase (PP5) that promotescellular proliferation by inhibiting both glucocorticoid and p53-mediated signaling pathways leading top21WAF1/Cip1-mediated growth arrest. The suppression of PP5 expression (1) markedly increases theassociation of GR with its cognate DNA-binding sequence, (2) induces GR transcriptional activity withoutthe addition of hormone, and (3) increases dexamethasone-mediated induction of GR reporter activity toa level that is ∼10 times greater than the maximal response obtainable in the presence of PP5. PP5 hasno apparent effect on the binding of hormone to the GR, and dexamethasone-mediated growth arrestcorrelates with an increase in p53 phosphorylation. Comparative studies in p53-wild-type, p53-defective,and p53-deficient cell lines indicate that either (1) p53 participates in GR-mediated induction of p21WAF1/Cip1,with the hyperphosphorylation of basal p53 induced by glucocorticoids sufficient for the propagation ofan antiproliferative response when PP5 expression is inhibited, or (2) PP5 acts where p53-mediated andGR-induced signaling networks converge to regulate the transcriptional induction of p21WAF1/Cip1. Thus,aberrant PP5 expression may have an additive effect on the development of human cancers by promotingcell proliferation via the inhibition of a GR-induced antiproliferative signaling cascade, and facilitatingneoplastic transformation via the inhibition of a growth-arresting p53-mediated response that guards againstgenomic instability.
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