Phosphorylation-Dependent Ubiquitination of Cyclin D1 by the SCFFBX4-αB Crystallin Complex

Douglas I. Lin, Olena Barbash, K. G.Suresh Kumar, Jason D. Weber, J. Wade Harper, Andres J J.P. Klein-Szanto, Anil Rustgi, Serge Y Y. Fuchs, J. Alan Diehl

Research output: Contribution to journalArticlepeer-review

314 Scopus citations


Growth factor-dependent accumulation of the cyclin D1 proto-oncogene is balanced by its rapid phosphorylation-dependent proteolysis. Degradation is triggered by threonine 286 phosphorylation, which promotes its ubiquitination by an unknown E3 ligase. We demonstrate that Thr286-phosphorylated cyclin D1 is recognized by a Skp1-Cul1-F box (SCF) ubiquitin ligase where FBX4 and αB crystallin govern substrate specificity. Overexpression of FBX4 and αB crystallin triggered cyclin D1 ubiquitination and increased cyclin D1 turnover. Impairment of SCFFBX4-αB crystallin function attenuated cyclin D1 ubiquitination, promoting cyclin D1 overexpression and accelerated cell-cycle progression. Purified SCFFBX4-αB crystallin catalyzed polyubiquitination of cyclin D1 in vitro. Consistent with a putative role for a cyclin D1 E3 ligase in tumorigenesis, FBX4 and αB crystallin expression was reduced in tumor-derived cell lines and a subset of primary human cancers that overexpress cyclin D1. We conclude that SCFFBX4-αB crystallin is an E3 ubiquitin ligase that promotes ubiquitin-dependent degradation of Thr286-phosphorylated cyclin D1.

Original languageEnglish
Pages (from-to)355-366
Number of pages12
JournalMolecular cell
Issue number3
StatePublished - Nov 3 2006




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