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Phosphorylation of MITF by AKT affects its downstream targets and causes TP53-dependent cell senescence

Chenyao Wang1, Lu Zhao2, Qian Su3

  • 1Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 20031, China.

The International Journal of Biochemistry & Cell Biology
|October 6, 2016
PubMed

Insights

Epidermal growth factor (EGF) impacts melanocyte proliferation via Microphthalmia-associated transcription factor (MITF) and TP53 interaction. Phosphorylated MITF (p-MITF-S510) levels may serve as a melanoma diagnostic marker.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Dermatology

Background:

  • Microphthalmia-associated transcription factor (MITF) is vital for melanocyte function, influencing melanogenesis and proliferation.
  • Its activity is modulated by abundance and post-translational modifications.
  • Epidermal growth factor (EGF) signaling is implicated in cellular processes, including senescence and proliferation.

Purpose of the Study:

  • To elucidate the regulatory mechanism of MITF in response to EGF stimulation.
  • To investigate the interaction between MITF, TP53, and AKT in melanocytes.
  • To assess the potential of phosphorylated MITF as a biomarker for melanoma.

Main Methods:

  • Western blotting to detect protein levels and phosphorylation status.
  • Immunoprecipitation assays to confirm protein-protein interactions.
  • Analysis of gene expression for CDKN1A and TYR.
  • Examination of p-MITF-S510 levels in human melanoma samples.

Main Results:

  • EGF induces senescence and cyclin-dependent kinase inhibitor 1A (CDKN1A) expression, linked to MITF.
  • MITF binds to TP53, regulating CDKN1A expression.
  • AKT phosphorylates MITF at S510, enhancing its affinity for TP53 and promoting CDKN1A expression.
  • Unphosphorylated MITF promotes TYR expression.
  • Low levels of phosphorylated MITF at S510 (p-MITF-S510) were observed in 90% of human melanoma samples.

Conclusions:

  • EGF stimulation triggers a signaling cascade involving AKT, MITF, and TP53 to regulate cell fate.
  • Phosphorylation of MITF at S510 by AKT is a key event in controlling CDKN1A expression and potentially senescence.
  • MITF's phosphorylation status dictates its role in either promoting proliferation (via TYR) or senescence (via CDKN1A).
  • The level of p-MITF-S510 presents a potential diagnostic marker for melanoma, offering insights into disease progression and therapeutic strategies.
Keywords:
AKTMITFPhosphorylationSenescenceTP53

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