Abstract A03: SCFCyclin F connects AKT signaling to the core cell cycle oscillator

Cell proliferation is governed by the presence of growth factors, and in their absence normal cells cease to progress through the cell cycle. The waves of Cyclin Dependent Kinase (CDK) activity constituting the core of the cell cycle oscillator are driven by cyclin synthesis and its subsequent destruction by the Anaphase Promoting Complex/Cyclosome (APC), a multi-subunit E3 ubiquitin ligase that controls degradation of Cyclins A and B. How growth factor signaling is integrated into the core cell cycle machinery remains largely elusive. Modular Cullin RING ubiquitin ligases (CRLs) represent the largest E3 ligase family in humans, and control the destruction of hundreds of proteins involved in virtually all aspects of cellular physiology. Here we establish a bi-directional ubiquitylation circuit between the APC substrate receptor Cdh1, and Cyclin F, a substrate receptor for the SCF (Skp1-Cul1-F box) family of CRL E3 ubiquitin ligases. We demonstrate that Cdh1 is regulated by SCF(Cyclin F), and conversely, Cyclin F is regulated by APC(Cdh1). AKT modulates the circuit by phosphorylating Cyclin F, enhancing SCF(Cyclin F) ligase assembly, and thereby catalyzing Cdh1 degradation. Later in the cell cycle, CDK phosphorylates Cdh1, preventing its degradation by altering its localization, and allowing both proteins to accumulate. The mutually antagonistic relationship between Cdh1 and Cyclin F represents the first described direct, reciprocal ubiquitylation circuit. Further, phospho-dep...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: G1 Advances: Novel Insights into G1 CDK/cyclins: Oral Presentations - Proffered Abstracts Source Type: research