The stress-activated protein kinases p38 alpha and JNK1 stabilize p21(Cip1) by phosphorylation.
Stress signals activate the SAPK/JNK and p38 MAPK classes of protein kinases, which mediate cellular responses, including steps in apoptosis and the maturation of some cell types. We now show that stress signals initiated by transforming growth factor-beta 1 (TGF-beta 1) induce G(1) arrest through protein stabilization of the CDK inhibitor p21(Cip1). TGF-beta 1 was previously shown to increase p21 protein levels, which in turn mediated G(1) arrest through inactivation of the CDK2-cyclin E complex in HD3 cells (Yan, Z., Kim, G.-Y., Deng, X., and Friedman, E. (2002) J. Biol. Chem. 277, 9870-9879). We now demonstrate that the increase in p21 abundance is caused by a post-transcriptional, SMAD-independent mechanism. TGF-beta1 activated p38 alpha and JNK1, which initiated the phosphorylation of p21. TGF-beta1 treatment increased the half-life of p21 by 3-4-fold. The increase in p21 stability was detected following activation of p38 alpha and JNK1, and treatment of cells with the p38 inhibitor SB203580 prevented this increase in p21 stability. p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro. Peptide mapping demonstrated that both TGF-beta 1 and p38 alpha induced phosphorylation of p21 at Ser(130) in vivo, and mutation of Ser(130) to alanine rendered p21 less stable than wild-type p21. TGF-beta 1 increased the stability of wild-type p21, but not the p21-S130A mutant. These findings demonstrate that SAPKs can mediate cell cycle arrest through post-translational modification of p21.
Kim
Geum-Yi
GY
Pathology Department, Upstate Medical University, Syracuse, New York 13210, USA.
Mercer
Stephen E
SE
Ewton
Daina Z
DZ
Yan
Zhongfa
Z
Jin
Kideok
K
Friedman
Eileen
E
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D048308:Mitogen-Activated Protein Kinase 14; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007093:Imidazoles; D011725:Pyridines; D016212:Transforming Growth Factor beta; D013912:Threonine; D012694:Serine; D048308:Mitogen-Activated Protein Kinase 14; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580