Reference SummaryLee EK, Mol Cell Biol 2013 Nov;33(22):4422-33

Title

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

Authors

Lee EK; Lian Z; D'Andrea K; Letrero R; Sheng W; Liu S; Diehl JN; Pytel D; Barbash O; Schuchter L; Amaravaradi R; Xu X; Herlyn M; Nathanson KL; Diehl JA

Journal

Mol Cell Biol

Volume

33

Issue

22

Year

2013

Pages

4422-33

Abstract

Cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6) dysregulation is a major contributor to melanomagenesis. Clinical evidence has revealed that p16(INK4A), an allosteric inhibitor of CDK4/6, is inactivated in over half of human melanomas, and numerous animal models have demonstrated that p16(INK4A) deletion promotes melanoma. FBXO4, a specificity factor for the E3 ligase that directs timely cyclin D1 proteolysis, has not been studied in melanoma. We demonstrate that Fbxo4 deficiency induces Braf-driven melanoma and that this phenotype depends on cyclin D1 accumulation in mice, underscoring the importance of this ubiquitin ligase in tumor suppression. Furthermore, we have identified a substrate-binding mutation, FBXO4 I377M, that selectively disrupts cyclin D1 degradation while preserving proteolysis of the other known FBXO4 substrate, TRF1. The I377M mutation and Fbxo4 deficiency result in nuclear accumulation of cyclin D1, a key transforming neoplastic event. Collectively, these data provide evidence that FBXO4 dysfunction, as a mechanism for cyclin D1 overexpression, is a contributor to human malignancy.

Links

J:206100 – Mouse Genome Informatics
24019069 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Braftm1Mmcm/+ Fbxo4tm1.1Jadi/+ Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte hyperplasia
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Muzzle

observed

[not specified]-Braftm1Mmcm/+ Fbxo4tm1.1Jadi Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte hyperplasia
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Muzzle

observed

[not specified]-Braftm1Mmcm/+ Fbxo4tm1.1Jadi/+ Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte melanoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

0

[not specified]-Braftm1Mmcm/+ Ccnd1tm1Wbg/+ Fbxo4tm1.1Jadi/+ Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte melanoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

0

[not specified]-Braftm1Mmcm/+ Ccnd1tm1Wbg Fbxo4tm1.1Jadi/+ Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte melanoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

0

[not specified]-Braftm1Mmcm/+ Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte melanoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

6.67

[not specified]-Braftm1Mmcm/+ Fbxo4tm1.1Jadi/+ Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte melanoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

73.33

[not specified]-Braftm1Mmcm/+ Fbxo4tm1.1Jadi Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte melanoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

70

[not specified]-Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte melanoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

0

[not specified] Skin - Melanocyte melanoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

0

[not specified]-Braftm1Mmcm/+ Ptentm2Mak Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte melanoma
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

observed

[not specified]-Braftm1Mmcm/+ Fbxo4tm1.1Jadi/+ Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte nevus - melanocytic
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

observed

[not specified]-Braftm1Mmcm/+ Fbxo4tm1.1Jadi Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte nevus - melanocytic
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

observed

[not specified]-Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

0

[not specified]-Braftm1Mmcm/+ Skin - Melanocyte tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

0

[not specified]-Braftm1Mmcm/+ Fbxo4tm1.1Jadi/+ Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

observed

[not specified]-Braftm1Mmcm/+ Fbxo4tm1.1Jadi Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

observed

[not specified]-Braftm1Mmcm/+ Tg(Tyr-cre/ERT2)13Bos Skin - Melanocyte tumor
  • 4-hydroxytamoxifen (4-OHT) (for inducing expression from mutant alleles)
Skin - Melanocyte

0