The Long-Lost Ligase: CRL4^AMBRA1 Regulates the Stability of D-Type Cyclins

Abstract

D-type cyclins (cyclin D1, D2, and D3, together cyclin D) are central drivers of the cell division cycle and well-described proto-oncoproteins. Rapid turnover of cyclin D is critical for its regulation, but the underlying mechanism has remained a matter of debate. Recently, AMBRA1 was identified as the major regulator of the stability of all three D-type cyclins. AMBRA1 serves as the substrate receptor for one of ∼40 CUL4-RING E3 ubiquitin ligase (CRL4) complexes to mediate the polyubiquitylation and subsequent degradation of cyclin D. Consequently, AMBRA1 regulates cell proliferation to impact tumor growth and the cellular response to cell cycle-targeted cancer therapies. Here we discuss the findings that implicate AMBRA1 as a core member of the cell cycle machinery.

D-Type Cyclins in Development and Disease

“…CRL4 AMBRA1 has been identified as the E3 ubiquitin ligase that ubiquitylates cyclin D, with ubiquitylation and degradation likely occurring in the nucleus [25][26][27]. Further complicating this is the observation of cyclin D degradation independent of GSK3ß, suggesting degradation pathways which are potentially mediated by other kinases [28][29][30].…”