Fbw7 and p53 cooperatively suppress advanced and chromosomally unstable intestinal cancer

Jonathan E. Grim, Sue E. Knoblaugh, Katherine A. Guthrie, Amanda Hagar, Jherek Swanger, Jessica Hespelt, Jeffrey J. Delrow, Tom Small, William M. Grady, Keiichi Nakayama, Bruce E. Clurman

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Colorectal cancer (CRC) remains a major cause of cancer mortality worldwide. Murine models have yielded critical insights into CRC pathogenesis, but they often fail to recapitulate advanced-disease phenotypes, notably metastasis and chromosomal instability (CIN). New models are thus needed to understand disease progression and to develop therapies. We sought to model advanced CRC by inactivating two tumor suppressors that are mutated in human CRCs, the Fbw7 ubiquitin ligase and p53. Here we report that Fbw7 deletion alters differentiation and proliferation in the gut epithelium and stabilizes oncogenic Fbw7 substrates, such as cyclin E and Myc. However, Fbw7 deletion does not cause tumorigenesis in the gut. In contrast, codeletion of both Fbw7 and p53 causes highly penetrant, aggressive, and metastatic adenocarcinomas, and allografts derived from these tumors form highly malignant adenocarcinomas. In vitro evidence indicates that Fbw7 ablation promotes genetic instability that is suppressed by p53, and we show that most Fbw7-/-; p53-/- carcinomas exhibit a CIN+phenotype. We conclude that Fbw7 and p53 synergistically suppress adenocarcinomas that mimic advanced human CRC with respect to histopathology, metastasis, and CIN. This model thus represents a novel tool for studies of advanced CRC as well as carcinogenesis associated with ubiquitin pathway mutations.

Original languageEnglish
Pages (from-to)2160-2167
Number of pages8
JournalMolecular and cellular biology
Volume32
Issue number11
DOIs
Publication statusPublished - Jun 1 2012

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Intestinal Neoplasms
Colorectal Neoplasms
Chromosomal Instability
Adenocarcinoma
Ubiquitin
Carcinogenesis
Neoplasm Metastasis
Phenotype
Cyclin E
Neoplasms
Ligases
Allografts
Disease Progression
Epithelium
Carcinoma
Mutation
Mortality

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Grim, J. E., Knoblaugh, S. E., Guthrie, K. A., Hagar, A., Swanger, J., Hespelt, J., ... Clurman, B. E. (2012). Fbw7 and p53 cooperatively suppress advanced and chromosomally unstable intestinal cancer. Molecular and cellular biology, 32(11), 2160-2167. https://doi.org/10.1128/MCB.00305-12

Fbw7 and p53 cooperatively suppress advanced and chromosomally unstable intestinal cancer. / Grim, Jonathan E.; Knoblaugh, Sue E.; Guthrie, Katherine A.; Hagar, Amanda; Swanger, Jherek; Hespelt, Jessica; Delrow, Jeffrey J.; Small, Tom; Grady, William M.; Nakayama, Keiichi; Clurman, Bruce E.

In: Molecular and cellular biology, Vol. 32, No. 11, 01.06.2012, p. 2160-2167.

Research output: Contribution to journalArticle

Grim, JE, Knoblaugh, SE, Guthrie, KA, Hagar, A, Swanger, J, Hespelt, J, Delrow, JJ, Small, T, Grady, WM, Nakayama, K & Clurman, BE 2012, 'Fbw7 and p53 cooperatively suppress advanced and chromosomally unstable intestinal cancer', Molecular and cellular biology, vol. 32, no. 11, pp. 2160-2167. https://doi.org/10.1128/MCB.00305-12
Grim JE, Knoblaugh SE, Guthrie KA, Hagar A, Swanger J, Hespelt J et al. Fbw7 and p53 cooperatively suppress advanced and chromosomally unstable intestinal cancer. Molecular and cellular biology. 2012 Jun 1;32(11):2160-2167. https://doi.org/10.1128/MCB.00305-12
Grim, Jonathan E. ; Knoblaugh, Sue E. ; Guthrie, Katherine A. ; Hagar, Amanda ; Swanger, Jherek ; Hespelt, Jessica ; Delrow, Jeffrey J. ; Small, Tom ; Grady, William M. ; Nakayama, Keiichi ; Clurman, Bruce E. / Fbw7 and p53 cooperatively suppress advanced and chromosomally unstable intestinal cancer. In: Molecular and cellular biology. 2012 ; Vol. 32, No. 11. pp. 2160-2167.
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