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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Regulation of CMGC kinases by hypoxia

  • KyeongJin Kim (Department of Biomedical Sciences, Program in Biomedical Science & Engineering and Research Center for Controlling Intercellular Communication (RCIC), Inha University College of Medicine) ;
  • Sang Bae Lee (Division of Life Sciences, Jeonbuk National University)
  • Received : 2023.08.20
  • Accepted : 2023.10.12
  • Published : 2023.11.30
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Abstract

Hypoxia, a widespread occurrence observed in various malignant tumors, results from rapid tumor growth that outpaces the oxygen supply. Tumor hypoxia precipitates several effects on tumor biology; these include activating angiogenesis, intensifying invasiveness, enhancing the survival of tumor cells, suppressing anti-tumor immunity, and fostering resistance to therapy. Aligned with the findings that correlate CMGC kinases with the regulation of Hypoxia-Inducible Factor (HIF), a pivotal modulator, reports also indicate that hypoxia governs the activity of CMGC kinases, including DYRK1 kinases. Prolyl hydroxylation of DYRK1 kinases by PHD1 constitutes a novel mechanism of kinase maturation and activation. This modification "primes" DYRK1 kinases for subsequent tyrosine autophosphorylation, a vital step in their activation cascade. This mechanism adds a layer of intricacy to comprehending the regulation of CMGC kinases, and underscores the complex interplay between distinct post-translational modifications in harmonizing precise kinase activity. Overall, hypoxia assumes a substantial role in cancer progression, influencing diverse aspects of tumor biology that include angiogenesis, invasiveness, cell survival, and resistance to treatment. CMGC kinases are deeply entwined in its regulation. To fathom the molecular mechanisms underpinning hypoxia's impact on cancer cells, comprehending how hypoxia and prolyl hydroxylation govern the activity of CMGC kinases, including DYRK1 kinases, becomes imperative. This insight may pave the way for pioneering therapeutic approaches that target the hypoxic tumor microenvironment and its associated challenges.

Keywords

Acknowledgement

This work was supported by an INHA UNIVERSITY Research Grant to K.K., and National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) to K.K. (RS-2023-00208008 and 2021R1A5A2031612), and S.B.L. (2020R1C1C1014281 and 2021R1A5A8029876).

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