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Molecular and Cellular Biology, June 2003, p. 3859-3871, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3859-3871.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Loss of Oncogenic H-ras-Induced Cell Cycle Arrest and p38 Mitogen-Activated Protein Kinase Activation by Disruption of Gadd45a

Dmitry V. Bulavin, Oleg Kovalsky, M. Christine Hollander, and Albert J. Fornace Jr.*

Gene Response Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

Received 16 October 2002/ Returned for modification 9 December 2002/ Accepted 11 March 2003

The activation of p53 is a guardian mechanism to protect primary cells from malignant transformation; however, the details of the activation of p53 by oncogenic stress are still incomplete. In this report we show that in Gadd45a-/- mouse embryo fibroblasts (MEF), overexpression of H-ras activates extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) but not p38 kinase, and this correlates with the loss of H-ras-induced cell cycle arrest (premature senescence). Inhibition of p38 mitogen-activated protein kinase (MAPK) activation correlated with the deregulation of p53 activation, and both a p38 MAPK chemical inhibitor and the expression of a dominant-negative p38{alpha} inhibited p53 activation in the presence of H-ras in wild-type MEF. p38, but not ERK or JNK, was found in a complex with Gadd45 proteins. The region of interaction was mapped to amino acids 71 to 96, and the central portion (amino acids 71 to 124) of Gadd45a was required for p38 MAPK activation in the presence of H-ras. Our results indicate that this Gadd45/p38 pathway plays an important role in preventing oncogene-induced growth at least in part by regulating the p53 tumor suppressor.

* Corresponding author. Mailing address: Building 37, Room 6144, NIH, Bethesda, MD 20892-4255. Phone: (301) 402-0745. Fax: (301) 480-1946. Email: fornace{at}nih.gov.

Molecular and Cellular Biology, June 2003, p. 3859-3871, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3859-3871.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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