NYMC Faculty Publications

Polo-like Kinase 3, Hypoxic Responses, and Tumorigenesis

DOI

10.1080/15384101.2017.1373224

Journal Title

Cell Cycle (Georgetown, Tex.)

First Page

2032

Last Page

2036

Document Type

Article

Publication Date

September 2017

Department

Pathology, Microbiology and Immunology

Abstract

The cellular hypoxic response contributes to cell transformation and tumor progression. Hypoxia-inducible factor 1 (HIF-1) is a key transcription factor that mediates transcription of genes whose products are essential for cellular adaptation to hypoxia. The activity of HIF-1 is largely regulated by the abundance of its alpha subunit (HIF-1alpha), which is primarily regulated by an oxygen-dependent and ubiquitin/proteasome-mediated degradation process. The HIF-1alpha protein level is also regulated by protein kinases through phosphorylation. Polo-like kinase 3 (Plk3) is a serine/threonine protein kinase with a tumor suppressive function. Plk3 phosphorylates and destabilizes HIF-1alpha. Plk3 also phosphorylates and stabilizes PTEN, a known regulator of HIF-1alpha stability via the PI3K pathway. Our latest study showed that the Plk3 protein is suppressed by hypoxia or nickel treatment via the ubiquitin/proteasome system. We discovered that Seven in Absentia Homologue 2 (SIAH2) is the E3 ubiquitin ligase of Plk3 and that Plk3 in turn destabilizes SIAH2. Given the role of SIAH2 in promoting stability of HIF-1alpha, our work reveals a novel mutual regulatory mechanism between Plk3 and SIAH2, which may function to fine-tune the cellular hypoxic response. Here we discuss the role of Plk3 in the hypoxic response and tumorigenesis in light of these latest findings.

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