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Title

SCF<sup>Fbl12</sup> Increases p21<sup>Waf1/Cip1</sup> Expression Level through Atypical Ubiquitin Chain Synthesis.

Authors

Fuminori Tsuruta; Ai Takebe; Kousuke Haratake; Yoshinori Kanemori; Jaehyun Kim; Tomoyuki Endo; Yu Kigoshi; Tomomi Fukuda; Hatsumi Miyahara; Manato Ebina; Tadashi Baba; Tomoki Chiba

Abstract

The cyclin-dependent kinase (CDK) inhibitor p21 is an unstructured protein regulated by multiple turnover pathways. p21 abundance is tightly regulated, and its defect causes tumor development. However, the mechanisms that underlie the control of p21 level are not fully understood. Here, we report a novel mechanism by which a component of the SCF ubiquitin ligase, Fbl12, augments p21 via the formation of atypical ubiquitin chains. We found that Fbl12 binds and ubiquitinates p21. Unexpectedly, Fbl12 increases the expression level of p21 by enhancing the mixed-type ubiquitination, including not only K48- but also K63-linked ubiquitin chains, followed by promotion of binding between p21 and CDK2. We also found that proteasome activator PA28γ attenuates p21 ubiquitination by interacting with Fbl12. In addition, UV irradiation induces a dissociation of p21 from Fbl12 and decreases K63-linked ubiquitination, leading to p21 degradation. These data suggest that Fbl12 is a key factor that maintains adequate intracellular concentration of p21 under normal conditions. Our finding may provide a novel possibility that p21's fate is governed by diverse ubiquitin chains.

Subjects

UBIQUITIN ligases; P21 gene; UBIQUITIN; UBIQUITINATION; PHYSIOLOGICAL effects of ultraviolet radiation

Publication

Molecular & Cellular Biology, 2016, Vol 36, Issue 16, p2182

ISSN

0270-7306

Publication type

Academic Journal

DOI

10.1128/MCB.00174-16