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Lin DI , Barbash O , Kumar KGS , Weber JD , Harper JW , Klein-Szanto AJP , Rustgi A , Fuchs SY , Diehl JA , Zamek-Gliszczynski MJ , Nezasa KI , Tian XB , Bridges AS , Lee K , Belinsky MG , Kruh GD , Brouwer KLR
Phosphorylation-dependent ubiquitination of cyclin D1 by the SCFFBX4-alpha B crystallin complex Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3(-)/(-) and Abcc4(-)/(-) mice
Molecular Cell. 2006 Dec;319(3) :1485-1491
PMID: ISI:000242048500054   
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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 alpha B crystallin govern substrate specificity. Overexpression of FBX4 and alpha B crystallin triggered cyclin D1 ubiquitination and increased cyclin D1 turnover. Impairment of SCFFBX4-alpha B crystallin function attenuated cyclin D1 ubiquitination, promoting cyclin D1 overexpression and accelerated cell-cycle progression. Purified SCFFBX4-alpha B crystallin catalyzed polyubiquitination of cyclin D1 in vitro. Consistent with a putative role for a cyclin D1 E3 ligase in tumorigenesis, FBX4 and alpha B crystallin expression was reduced in tumor-derived cell lines and a subset of primary human cancers that overexpress cyclin D1. We conclude that SCFFBX4-alpha B crystallin is an E3 ubiquitin ligase that promotes ubiquitin-dependent degradation of Thr286-phosphorylated cyclin D1. C1 Univ Penn, Leonard & Madlyn Abramson Family Canc Res Inst &, Philadelphia, PA 19104 USA. Univ Penn, Dept Canc Biol, Philadelphia, PA 19104 USA. Univ Penn, Dept Anim Biol, Philadelphia, PA 19104 USA. Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA.
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