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Molecular and Cellular Biology, May 2007, p. 3530-3541, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.00086-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Negative Regulation of ASK1 by p21^Cip1 Involves a Small Domain That Includes Serine 98 That Is Phosphorylated by ASK1 In Vivo ^,

Jun Zhan,¹ John B. Easton,¹ Shile Huang,² Ashutosh Mishra,³ Limin Xiao,⁴ Eilyn R. Lacy,^4, Richard W. Kriwacki,⁴ and Peter J. Houghton^1*

Department of Molecular Pharmacology,¹ Hartwell Center,³ Department of Structural Biology, St. Jude Children's Research Hospital, 332 North Lauderdale St., Memphis, Tennessee 38105-2794,⁴ Department of Biochemistry & Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, Louisiana 71130-3932²

Received 13 January 2007/ Returned for modification 13 February 2007/ Accepted 18 February 2007

The cyclin-dependent kinase inhibitor p21^Cip1 regulates multiple cellular functions and protects cells from genotoxic and other cellular stresses. Activation of apoptosis signal-regulating kinase 1 (ASK1) induced by inhibition of mTOR signaling leads to sustained phospho-c-Jun that is suppressed in cells with functional p53 or by forced expression of p21^Cip1. Here we show that small deletions of p21^Cip1 around S98 abrogate its association with ASK1 but do not affect binding to Cdk1, hence distinguishing between the cell cycle-regulating functions of p21^Cip1 and its ability to suppress activation of the ASK1/Jun N-terminal protein kinase (JNK) pathway. p21^Cip1 is phosphorylated in vitro by both ASK1 and JNK1 at S98. In vivo phosphorylation of p21^Cip1, predominantly carried out by ASK1, is associated with binding to ASK1 and inactivation of ASK1 kinase function. Binding of p21^Cip1 to ASK1 requires ASK1 kinase function and may involve phosphorylation of S98.

Published ahead of print on 26 February 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Centocor, Inc., 145 King of Prussia Road, Radnor, PA 19087.

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