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Published on: October 4, 2019

A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma

Zhi Sheng1, Li Li, Lihua J Zhu

  • 1Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Nature Medicine
|May 25, 2010
PubMed

Insights

Activating transcription factor-5 (ATF5) is crucial for malignant glioma survival. A newly identified pathway involving CREB3L2 activates ATF5, promoting cancer cell survival and poor prognosis, offering new therapeutic targets.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Activating transcription factor-5 (ATF5) is upregulated in malignant glioma.
  • ATF5 plays a critical role in promoting cancer cell survival.
  • Identifying regulators of ATF5 is key to understanding glioma pathogenesis.

Purpose of the Study:

  • To identify transcriptional regulators of ATF5 in malignant glioma.
  • To elucidate the signaling pathway that controls ATF5 expression.
  • To explore ATF5 as a therapeutic target for glioma.

Main Methods:

  • Genome-wide RNA interference (RNAi) screen.
  • Analysis of signaling cascades (RAS-MAPK, PI3K).
  • Assessment of ATF5 expression in human glioma samples and mouse models.

Main Results:

  • A novel survival pathway was identified: RAS-MAPK/PI3K activates CREB3L2, which induces ATF5.
  • ATF5 promotes survival by upregulating the antiapoptotic gene MCL1.
  • High ATF5 expression correlates with poor prognosis in human malignant glioma.
  • Sorafenib, a RAF kinase inhibitor, reduces ATF5 expression and inhibits glioma growth.

Conclusions:

  • ATF5 is essential for malignant glioma development and survival.
  • The identified ATF5-mediated pathway represents a potential therapeutic strategy for glioma.
  • Targeting ATF5 could offer a novel approach to treating malignant glioma.

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