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Protein Kinase C Isoforms Differentially Regulate Hypoxia-Inducible Factor-1α Accumulation in Cancer Cells.

Authors
  • Kim, Hyunju1
  • Na, Yu-Ran1
  • Kim, So Yeon1, 2
  • Yang, Eun Gyeong1, 3
  • 1 Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, South Korea. , (North Korea)
  • 2 Department of Biomedical Engineering, Korea University of Science and Technology (UST), KIST campus, Seoul 136-791, South Korea. , (North Korea)
  • 3 Department of Biological Chemistry, Korea University of Science and Technology (UST), KIST campus, Seoul 136-791, South Korea. , (North Korea)
Type
Published Article
Journal
Journal of Cellular Biochemistry
Publisher
Wiley (John Wiley & Sons)
Publication Date
March 2016
Volume
117
Issue
3
Pages
647–658
Identifiers
DOI: 10.1002/jcb.25314
PMID: 26284819
Source
Medline
Keywords
License
Unknown

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is one of the key transcription factors that mediate adaptation to hypoxia. Despite increasing evidence implicating the PKC family as potential modulators of HIF-1α, the molecular mechanisms of PKC isoform-dependent HIF-1α activity under hypoxic conditions have not been systematically elucidated in cancer cell lines. Here, we collectively investigated how each isoform of the PKC family contributes to HIF-1α accumulation in the human cervical cancer cell line HeLa. Among the abundant PKC isoforms, blockade of either PKCα or PKCδ was found to substantially reduce HIF-1α accumulation and transcriptional activity in hypoxic cells. Knockdown of PKCδ resulted in a reduction of HIF-1α mRNA levels, whereas the HIF-1α mRNA level was unchanged regardless of PKCα knockdown. Upon searching for the downstream effectors of these kinases, we found that PKCα controls HIF-1α translation via AKT-mTOR under hypoxic conditions. On the other hand, one of the well-known transcriptional regulation pathways of HIF-1α, nuclear factor-κB (NF-κB) is identified as a downstream effector of PKCδ. Taken together, our findings provide insights into the roles of PKC isoforms as additional, discrete modulators of hypoxia-stimulated HIF-1α accumulation through different signaling pathways.

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