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Updated: Aug 25, 2025

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Early growth response-1 is a new substrate of the GSK3β-FBXW7 axis

Lu Yin1, Jiagui Zhang1, Yi Sun2

  • 1Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.

Neoplasia (New York, N.Y.)
|October 14, 2022
PubMed

Insights

The study identifies FBXW7 as a novel E3 ligase for EGR1, a key factor in cell proliferation and tumor growth. This discovery reveals a new regulatory axis involving GSK3β and FBXW7 that impacts cancer cell growth.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • Early growth response 1 (EGR1) is a transcription factor regulating cell proliferation and tumor progression.
  • The precise regulation of EGR1 by Cullin-RING ligases (CRLs) has not been fully elucidated.
  • Understanding EGR1 regulation is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of CRLs in EGR1 regulation.
  • To identify the specific E3 ligase responsible for EGR1 degradation.
  • To elucidate the functional consequences of EGR1 regulation in cancer cells.

Main Methods:

  • Utilized MLN4924, a neddylation inhibitor, to assess EGR1 stability.
  • Employed siRNA-mediated knockdown and overexpression of FBXW7 to study its effect on EGR1 levels.
  • Investigated the interaction between FBXW7 and EGR1 using binding assays and mutant analysis.
  • Assessed the role of GSK3β kinase in the FBXW7-EGR1 regulatory axis.
  • Evaluated the impact of EGR1 and FBXW7 modulation on cancer cell growth.

Main Results:

  • Identified SCFFBXW7 (CRL1) as a novel E3 ligase for EGR1.
  • Demonstrated that FBXW7 binds to EGR1 via a specific degron, and cancer-derived FBXW7 mutants exhibit reduced binding.
  • Showed that FBXW7 knockdown leads to EGR1 accumulation and extended protein half-life, while FBXW7 overexpression promotes EGR1 polyubiquitylation.
  • Established that GSK3β kinase is essential for FBXW7-mediated EGR1 degradation.
  • Found that hypoxia enhances FBXW7-EGR1 interaction and subsequent EGR1 degradation.
  • Confirmed that EGR1 knockdown suppresses cancer cell growth, and FBXW7 knockdown-induced growth is partially dependent on EGR1.

Conclusions:

  • EGR1 is a novel substrate of the GSK3β-FBXW7 regulatory axis.
  • The FBXW7-EGR1 pathway plays a significant role in coordinating cancer cell growth.
  • Targeting the FBXW7-EGR1 axis presents a potential therapeutic strategy for cancer treatment.
Keywords:
Cullin-RING ligase (CRL)EGR1FBXW7GSK3βUbiquitylation

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