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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

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MageC2 protein is upregulated by oncogenic activation of MAPK pathway and causes impairment of the p53

Franco Andrés Pascucci1, María Fátima Ladelfa1, María Fernanda Toledo1

  • 1Lab. Oncología Molecular, Departamento de Química Biológica and IQUIBICEN-UBA/CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.

Biochimica Et Biophysica Acta. Molecular Cell Research
|December 6, 2020
PubMed

Insights

MageC2 protein accumulates with MEK/ERK pathway activation, promoting cancer by suppressing the p53 tumor suppressor. Inhibiting this pathway reduces MageC2, offering a potential therapeutic strategy for cancers with Ras or B-Raf mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Signal Transduction

Background:

  • Cancer development involves altered gene expression and signaling pathways that evade tumor suppressor gene activity.
  • The p53 tumor suppressor is crucial for preventing cancer, and its regulation is often disrupted in malignant cells.

Purpose of the Study:

  • To investigate the role of MageC2 protein in regulating the p53 tumor suppressor in the context of MEK/ERK MAPK pathway activation.
  • To determine if MageC2 is a functional target of oncogenic signaling pathways in melanoma.

Main Methods:

  • Utilized cell culture models with oncogenic mutations (H-RasV12, B-RafV600E) and MEK/ERK pathway inhibitors.
  • Employed CRISPR/Cas9 technology to generate MageC2 knockout cell lines.
  • Analyzed MageC2 protein levels and p53 transcriptional activity.
  • Performed gene expression analysis on cancer-genomic databases.

Main Results:

  • MageC2 protein accumulates upon MEK/ERK MAPK activation, as seen with H-RasV12 oncogene expression.
  • MEK inhibitors reduced MageC2 levels in melanoma cells with B-RafV600E mutations.
  • MageC2 knockout cells showed reduced p53 transcriptional activity when MEK/ERK signaling was hyperactive.
  • Cancer-genomic data correlated reduced p53 activity with high MageC2 expression in melanomas harboring Ras or B-Raf mutations.

Conclusions:

  • MageC2 protein accumulation is linked to oncogenic MEK/ERK pathway activation.
  • MageC2 plays a role in suppressing p53 transcriptional activity in hyperactive MEK/ERK signaling environments.
  • MageC2 may serve as a functional target of the MEK/ERK pathway in melanoma development.
Keywords:
B-RafH-RasMAGEMAPKMelanomaOncogenesp53

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