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Supplementary Figure 1 from Pirh2 Promotes Ubiquitin-Dependent Degradation of the Cyclin-Dependent Kinase Inhibitor p27Kip1

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posted on 2023-03-30, 17:42 authored by Takayuki Hattori, Tomoyasu Isobe, Kenji Abe, Hirotoshi Kikuchi, Kyoko Kitagawa, Toshiaki Oda, Chiharu Uchida, Masatoshi Kitagawa
Supplementary Figure 1 from Pirh2 Promotes Ubiquitin-Dependent Degradation of the Cyclin-Dependent Kinase Inhibitor p27Kip1

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ARTICLE ABSTRACT

The cyclin-dependent kinase inhibitor p27Kip1 is degraded in late G1 phase by the ubiquitin-proteasome pathway, allowing cells to enter S phase. Due to accelerated degradation of p27Kip1, various human cancers express low levels of p27Kip1 associated with poor prognosis. S-phase kinase–associated protein 2, the F-box protein component of an SCF ubiquitin ligase complex, is implicated in degradation of p27Kip1 during S-G2 phases. Recently, Kip1 ubiquitination–promoting complex has been reported as another ubiquitin ligase that targets cytoplasmic p27Kip1 exported from the nucleus in G0-G1 phases. Here, we identified a RING-H2–type ubiquitin ligase, Pirh2, as a p27Kip1-interacting protein. Endogenous Pirh2 physically interacted with endogenous p27Kip1 in mammalian cells. Pirh2 directly ubiquitinated p27Kip1 in an intact RING finger domain-dependent manner in vivo, as well as in vitro. Ablation of endogenous Pirh2 by small interfering RNA increased the steady-state level of p27Kip1 and decelerated p27Kip1 turnover. Depletion of Pirh2 induced accumulation of p27Kip1 in both the nucleus and cytoplasm. Pirh2 expression was induced from late G1-S phase, whereas p27Kip1 was decreased in synchronization with accumulation of Pirh2. Furthermore, reduction of Pirh2 resulted in an impairment of p27Kip1 degradation and an inhibition of cell cycle progression at G1-S transition in a p53-independent manner. Overall, the results indicate that Pirh2 acts as a negative regulator of p27Kip1 function by promoting ubiquitin-dependent proteasomal degradation. [Cancer Res 2007;67(22):10789–95]

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