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Updated: May 8, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

The FBXO4 tumor suppressor functions as a barrier to BRAFV600E-dependent metastatic melanoma

Eric K Lee1, Zhaorui Lian, Kurt D'Andrea

  • 1The Leonard and Madlyn Abramson Family Cancer Research Institute.

Molecular and Cellular Biology
|September 11, 2013
PubMed

Insights

FBXO4 deficiency and a specific mutation promote melanoma by causing cyclin D1 accumulation. This highlights FBXO4

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Dysregulation of Cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6) is crucial in melanoma development.
  • p16(INK4A) inactivation is common in human melanomas and promotes melanoma in animal models.
  • The role of FBXO4, an E3 ligase specificity factor for cyclin D1 degradation, in melanoma is unexplored.

Purpose of the Study:

  • To investigate the role of FBXO4 in melanoma development.
  • To determine if FBXO4 deficiency or mutations contribute to melanoma by affecting cyclin D1 proteolysis.

Main Methods:

  • Studied the effects of Fbxo4 deficiency in mouse models of Braf-driven melanoma.
  • Identified and characterized a specific FBXO4 substrate-binding mutation (I377M) affecting cyclin D1 degradation.
  • Assessed the impact of FBXO4 deficiency and the I377M mutation on cyclin D1 and TRF1 proteolysis and localization.

Main Results:

  • Fbxo4 deficiency in mice induced Braf-driven melanoma, dependent on cyclin D1 accumulation.
  • A novel FBXO4 I377M mutation selectively impaired cyclin D1 degradation while sparing TRF1 degradation.
  • Both Fbxo4 deficiency and the I377M mutation led to nuclear accumulation of cyclin D1, promoting neoplastic transformation.

Conclusions:

  • FBXO4 functions as a tumor suppressor in melanoma by mediating cyclin D1 degradation.
  • FBXO4 dysfunction, leading to cyclin D1 overexpression, is a contributing mechanism in human melanoma.
  • Targeting FBXO4 or stabilizing its function may offer therapeutic strategies for melanoma.

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