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Identification of both Myt‐1 and Wee‐1 as necessary mediators of the p21‐independent inactivation of the cdc‐2/cyclin B1 complex and growth inhibition of TRAMP cancer cells by genistein
Author(s) -
Touny Lara H. El,
Banerjee Partha P.
Publication year - 2006
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20495
Subject(s) - cyclin dependent kinase 1 , genistein , cyclin b1 , tramp , cell growth , kinase , cell cycle , cancer research , biology , microbiology and biotechnology , chemistry , apoptosis , endocrinology , cancer , biochemistry , prostate cancer , genetics
BACKGROUND The G 2 /M cell‐cycle arrest is one mechanism by which genistein exerts its anti‐proliferative effects, and the proposed underlying causes encompass the transcriptional repression of cyclin B1 and the activation of p21. However, the involvement of upstream kinases Myt‐1 and Wee‐1 in this arrest remains to be elucidated. METHODS Myt‐1 and Wee‐1 modulation by genistein was examined via Western blot analysis and the effect of their inhibition by siRNA on cyclin B1 levels/localization, cdc2 kinase activity, and cellular proliferation of genistein‐treated TRAMP‐C2 cells was determined. RESULTS The sustained G 2 /M arrest by genistein in TRAMP‐C2 cells is associated with increased phospho‐cdc2(Tyr15), decreased cdc2 protein, and cytoplasmic retention of cyclinB1, resulting in decreased cdc2 kinase activity independently of p21. Genistein treatment increased Myt‐1 levels and decreased Wee‐1 phosphorylation. Downregulation of Myt‐1 and Wee‐1 by siRNA restored cdc2 levels, its kinase activity, cyclinB1 nuclear localization, and partially restored cell proliferation of genistein‐treated cells. CONCLUSIONS Myt‐1 and Wee‐1 rather than p21 are necessary for genistein‐induced G 2 /M arrest in TRAMP‐C2 cells and their inhibition partially restores proliferation of TRAMP‐C2 cells in the presence of genistein. Prostate 66: 1542–1555, 2006. © 2006 Wiley‐Liss, Inc.