Journal
LEUKEMIA
Volume 27, Issue 5, Pages 1053-1062Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2012.361
Keywords
FBXW7; T-ALL; glucocorticoid receptor; ubiquitylation
Categories
Funding
- National Health and Medical Research Council of Australia
- Cancer Council New South Wales
- Steven Walter Children's Cancer Foundation
- Cancer Institute New South Wales
- Leukemia Foundation
- Swedish Society for Medical Research
- Swedish Cancer Foundation
- Swedish Research Council
- Swedish Children's Cancer Foundation
- Karolinska Institute Foundations
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Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor alpha (GR alpha) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 beta-mediated phsophorylation. FBXW7 inactivation caused elevated GR alpha levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GR alpha as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GR alpha levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.
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