Mutual regulation between Polo-like kinase 3 and SIAH2 E3 ubiquitin ligase defines a regulatory network that fine-tunes the cellular response to hypoxia and nickel.

The Journal of Biological Chemistry
Cen LiDazhong Xu

Abstract

Elevated cellular response to hypoxia, which contributes to cell transformation and tumor progression, is a prominent feature of malignant cells in solid tumors. Polo-like kinase 3 (Plk3) is a serine/threonine protein kinase known to inhibit the cellular response to hypoxia and tumorigenesis. Nickel compounds are well-established human carcinogens that induce tumorigenesis partly through their hypoxia-mimicking effects. Despite previous research efforts, the role of Plk3 in the hypoxic response induced by hypoxia or nickel is not completely understood. Here, we show that NiCl2 (Ni(II)) or hypoxia reduces the protein level and shortens the half-life of cytoplasmic Plk3 in a ubiquitin-proteasome-dependent manner. We identify SIAH2, a RING finger E3 ubiquitin ligase associated with the cellular hypoxic response, to be the ubiquitin E3 ligase that mediates the degradation of Plk3. We show that SIAH2 binds to Plk3 and mediates its ubiquitination primarily through its polo-box domain. We report that USP28, a deubiquitinase known to be inhibitable by Ni(II) or hypoxia, may also contribute to the suppression of the Plk3 protein by Ni(II). We also show that Plk3 in turn suppresses the SIAH2 protein level in a kinase activity-dependent m...Continue Reading

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Citations

Sep 1, 2017·Cell Cycle·Dazhong XuCen Li
Apr 5, 2018·The EMBO Journal·Marc Segarra-MondejarFrancesc X Soriano
Jan 9, 2020·Nature Communications·Marzia ScortegagnaZe'ev A Ronai
Nov 11, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Christopher A RaabKlaus Strebhardt
Jan 2, 2021·International Journal of Molecular Sciences·Adam AlbaneseViolaine Sée
Apr 13, 2021·Frontiers in Cell and Developmental Biology·Dazhong Xu, Cen Li
Jun 3, 2021·Plants·Catherine M Doorly, Emmanuelle Graciet
Oct 24, 2021·Gene·Kailang LiXiaofeng Jin

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