CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth

Noel A. Warfel, Nathan G. Dolloff, David T. Dicker, Jozef Malysz, Wafik S. El-Deiry

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a major mediator of tumor physiology, and its activation is correlated with tumor progression, metastasis, and therapeutic resistance. HIF-1 is activated in a broad range of solid tumors due to intratumoral hypoxia or genetic alterations that enhance its expression or inhibit its degradation. As a result, decreasing HIF-1α expression represents an attractive strategy to sensitize hypoxic tumors to anticancer therapies. Here, we show that cyclin-dependent kinase 1 (CDK1) regulates the expression of HIF-1α, independent of its known regulators. Overexpression of CDK1 and/or cyclin B1 is sufficient to stabilize HIF-1α under normoxic conditions, whereas inhibition of CDK1 enhances the proteasomal degradation of HIF-1α, reducing its half-life and steady-state levels. In vitro kinase assays reveal that CDK1 directly phosphorylates HIF-1α at a previously unidentified regulatory site, Ser668. HIF-1α is stabilized under normoxic conditions during G2/M phase via CDK1-mediated phosphorylation of Ser668. A phospho-mimetic construct of HIF-1α at Ser668 (S668E) is significantly more stable under both normoxic and hypoxic conditions, resulting in enhanced transcription of HIF-1 target genes and increased tumor cell invasion and migration. Importantly, HIF-1α (S668E) displays increased tumor angiogenesis, proliferation, and tumor growth in vivo compared with wild-type HIF-1α. Thus, we have identified a novel link between CDK1 and HIF-1α that provides a potential molecular explanation for the elevated HIF-1 activity observed in primary and metastatic tumors, independent of hypoxia, and offers a molecular rationale for the clinical translation of CDK inhibitors for use in tumors with constitutively active HIF-1.

Original languageEnglish (US)
Pages (from-to)3689-3701
Number of pages13
JournalCell Cycle
Volume12
Issue number23
DOIs
StatePublished - Dec 1 2013

Fingerprint

CDC2 Protein Kinase
Hypoxia-Inducible Factor 1
Phosphorylation
Growth
Neoplasms
Cyclin B1
G2 Phase

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Warfel, N. A., Dolloff, N. G., Dicker, D. T., Malysz, J., & El-Deiry, W. S. (2013). CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth. Cell Cycle, 12(23), 3689-3701. https://doi.org/10.4161/cc.26930
Warfel, Noel A. ; Dolloff, Nathan G. ; Dicker, David T. ; Malysz, Jozef ; El-Deiry, Wafik S. / CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth. In: Cell Cycle. 2013 ; Vol. 12, No. 23. pp. 3689-3701.
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Warfel, NA, Dolloff, NG, Dicker, DT, Malysz, J & El-Deiry, WS 2013, 'CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth', Cell Cycle, vol. 12, no. 23, pp. 3689-3701. https://doi.org/10.4161/cc.26930

CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth. / Warfel, Noel A.; Dolloff, Nathan G.; Dicker, David T.; Malysz, Jozef; El-Deiry, Wafik S.

In: Cell Cycle, Vol. 12, No. 23, 01.12.2013, p. 3689-3701.

Research output: Contribution to journalArticle

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T1 - CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth

AU - Warfel, Noel A.

AU - Dolloff, Nathan G.

AU - Dicker, David T.

AU - Malysz, Jozef

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