The Cell Cycle-regulated B-Myb Transcription Factor Overcomes Cyclin-dependent Kinase Inhibitory Activity of p57KIP2 by Interacting with Its Cyclin-binding Domain

• Published in: The Journal of biological chemistry Vol. 278; no. 45; p. 44255
• Main Authors: Manel Joaquin, Roger J. Watson
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 07.11.2003
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M308953200

The cell cycle-regulated B-Myb transcription factor is required for early embryonic development and is implicated in regulating cell growth and differentiation. In addition to its transcriptional regulatory properties, recent data indicate that B-Myb can release active cyclin/Cdk2 activity from the retinoblastoma-related p107 protein by directly interacting with the p107 N terminus. As this p107 domain has homology to the cyclin-binding domains of the p21 Waf1/Cip1 family of cyclin-dependent kinase inhibitors (CKIs), we investigated in this study whether B-Myb could also interact with these CKIs. No in vivo interaction was found with either p21 Waf1/Cip1 or p27 KIP1 , however, binding to p57 KIP2 was readily detectable in both in vivo and in vitro assays. The B-Myb-interacting region of p57 KIP2 mapped to the cyclin-binding domain. Consistent with this, B-Myb competed with cyclin A2 for binding to p57 KIP2 , resulting in release of active cyclin/Cdk2 kinase. Moreover, B-Myb partially overcame the ability of p57 KIP2 to induce G 1 arrest in Saos-2 cells. Despite similarities with previous p107 studies, the B-Myb domains required for interaction with p57 KIP2 were quite different from those implicated for p107. Thus, it is evident that B-Myb may promote cell proliferation by a non-transcriptional mechanism that involves release of active cyclin/Cdk2 from p57 KIP2 as well as p107.