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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.

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* Corresponding author. Mailing address: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 North Lauderdale St., Memphis, TN 38105-2794. Phone: (901) 495-3440. Fax: (901) 495-4290. E-mail: peter.houghton{at}stjude.org

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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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.

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