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Vol. 19, Issue 9, 3667-3675, September 2008

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Transcriptional Regulation of Serine/Threonine Kinase-15 (STK15) Expression by Hypoxia and HIF-1

Department of Biochemistry, Faculty of Chemistry, University of Kaiserslautern, D-67663 Kaiserslautern, Germany

Submitted January 17, 2008; Revised April 29, 2008; Accepted June 5, 2008
Monitoring Editor: William P. Tansey

The serine/threonine kinase-15 (STK15) acts as a cell cycle regulator being overexpressed in various tumors. One mechanism that could contribute to overexpression of STK15 is tumor hypoxia where hypoxia-inducible factor-1 (HIF-1) is a major regulator of transcription. Therefore, we analyzed whether hypoxia and HIF-1 could contribute to overexpression of STK15. We found that hypoxia increased STK15 expression and STK15 promoter activity in HepG2 tumor cells. Overexpression of HIF-1 induced STK15 gene transcription, whereas HIF-1 siRNA and overexpression of prolyl hydroxylase 2 (PHD-2), a negative regulator of HIF-1, reversed this effect. In addition, site-directed mutagenesis experiments and chromatin immunoprecipitation revealed that from the three putative hypoxia responsive elements (HRE) within the STK15 promoter only HRE-2 was functional and bound HIF-1. Further, siRNA against STK15 inhibited proliferation of HepG2 cells induced by hypoxia. These results show that STK15 gene transcription can be regulated by hypoxia and HIF-1 via HRE-2 of the STK15 promoter. Thus, tumor hypoxia may trigger overexpression of STK15 observed in various tumors.

Address correspondence to: Thomas Kietzmann (tkietzm{at}gwdg.de)

Abbreviations used: ARNT, arylhydrocarbon receptor nuclear translocator protein; CDC-2, cell division cycle 2; CIN, chromosomal instability; c-MET, Met proto-oncogene; CXCR4, chemokine receptor 4; E4TF-1, Ets transcription factor 1; GABP, GA-binding protein transcription factor; HIF-1, hypoxia-inducible factor 1; HRE, hypoxia responsive element; PAI-1, plasminogen activator inhibitor 1; PGI, phosphoglucose isomerase; PHD, prolyl hydroxylase; RB-1, retinoblastoma 1; STK15, serine/threonine kinase 15; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau tumor suppressor protein.