| Literature DB >> 17081987 |
Douglas I Lin1, Olena Barbash, K G Suresh Kumar, Jason D Weber, J Wade Harper, Andres J P Klein-Szanto, Anil Rustgi, Serge Y Fuchs, J Alan Diehl.
Abstract
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 alphaB crystallin govern substrate specificity. Overexpression of FBX4 and alphaB crystallin triggered cyclin D1 ubiquitination and increased cyclin D1 turnover. Impairment of SCF(FBX4-alphaB crystallin) function attenuated cyclin D1 ubiquitination, promoting cyclin D1 overexpression and accelerated cell-cycle progression. Purified SCF(FBX4-alphaB crystallin) catalyzed polyubiquitination of cyclin D1 in vitro. Consistent with a putative role for a cyclin D1 E3 ligase in tumorigenesis, FBX4 and alphaB crystallin expression was reduced in tumor-derived cell lines and a subset of primary human cancers that overexpress cyclin D1. We conclude that SCF(FBX4-alphaB crystallin) is an E3 ubiquitin ligase that promotes ubiquitin-dependent degradation of Thr286-phosphorylated cyclin D1.Entities:
Mesh：
Substances：
Year: 2006 PMID： 17081987 PMCID： PMC1702390 DOI： 10.1016/j.molcel.2006.09.007
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970