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Molecular and Cellular Biology, December 2003, p. 8890-8901, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8890-8901.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Transcriptional Repressor HBP1 Is a Target of the p38 Mitogen-Activated Protein Kinase Pathway in Cell Cycle Regulation

Mei Xiu,1,2 Jiyoung Kim,1,2 Ellen Sampson,1 Chun-Yin Huang,1,2 Roger J. Davis,3 K. Eric Paulson,1,2 and Amy S. Yee1*

Department of Biochemistry, School of Medicine,1 School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts 02111,2 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 016053

Received 9 May 2003/ Returned for modification 2 June 2003/ Accepted 26 August 2003

The p38 mitogen-activated protein (MAP) kinase signaling pathway participates in both apoptosis and G1 arrest. In contrast to the established role in apoptosis, the documented induction of G1 arrest by activation of the p38 MAP kinase pathway has attracted recent attention with reports of substrates that are linked to cell cycle regulation. Here, we identify the high-mobility group box protein HBP1 transcriptional repressor as a new substrate for p38 MAP kinase. Our previous work had shown that HBP1 inhibits G1 progression in cell and animal models, and thus indicated that HBP1 could be a relevant substrate for p38 MAP kinase in cell cycle regulation. In the present work, a p38 MAP kinase docking site (amino acids [aa] 81 to 125) and a p38 MAP kinase phosphorylation site (serine 401) were identified in the HBP1 protein. Furthermore, the docking and phosphorylation sites on HBP1 were specific for p38 MAP kinase. In defining the role of p38 MAP kinase regulation, the inhibition of p38 MAP kinase activity was shown to decrease HBP1 protein levels by triggering protein instability, as manifested by a decrease in protein half-life. Consistently, a decrease in protein levels was accompanied by a decrease in overall DNA binding activity. A mutation of the p38 MAP kinase phosphorylation site at aa 401 [(S-A)401HBP1] also triggered HBP1 protein instability. While protein stability was compromised by mutation, the specific activities of (S-A)401HBP1 and of wild-type HBP1 appeared comparable for transcriptional repression. This comparison of transcription-specific activity highlighted that p38 MAP kinase regulated HBP1 protein levels but not the intrinsic activity for DNA binding or for transcriptional repression. Finally, p38 MAP kinase-mediated regulation of the HBP1 protein also contributed to the regulation of G1 progression. Together, our work supports a molecular framework in which p38 MAP kinase activity contributes to cell cycle inhibition by increasing HBP1 and other G1 inhibitory factors by regulating protein stability.

* Corresponding author. Mailing address: Department of Biochemistry, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. Phone: (617) 636-6850. Fax: (617) 636-2409. E-mail: amy.yee{at}tufts.edu.

Molecular and Cellular Biology, December 2003, p. 8890-8901, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8890-8901.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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