FOXOSa, a member of the forkhead family of transcription factors, is proposed to be a tumor suppressor protein through its ability to control apoptotic cell death and inhibition of cell proliferation. The various functions of FOXO family members are subject to tight regulatory control through posttranslational mechanisms such as reversible phosphorylation and ubiquitination. Many direct regulators of FOXOSa posttranslational modification, however, such as components of the ubiquitination machinery are still not well characterized. We and others have recently established that Bcr-Abl, the primary cause of chronic myelogenous leukemia (CML), negatively regulates FOXOSa and its proapoptotic targets, TRAIL and Bim, to promote evasion of transformed cells from apoptosis. Our cell culture, in vivo mice studies and studies with patient samples have demonstrated that one mechanism by which Bcr-Abl regulates FOXOSa is via the proteasomal degradation pathway. As the emergence of resistance to imatinib (IM) warrants the search for alternative therapeutic strategies, I propose that downstream components of the Bcr-Abl/PISK/AKT signaling module that directly regulate FOXOSa function are novel targets in the treatment of CML. The main hypothesis of this proposal is that Bcr-Abl-induced down-regulation of FOXOSa is an essential mechanism to promote cellular transformation and leukemogenesis.
The specific aims of this proposal are twofold. First, to determine the biological significance of FOXOSa activity in promoting Bcr-Abl-induced transformation of hematopoietic cells. Second, to direct efforts toward understanding the molecular mechanisms for Bcr-Abl-induced suppression of FOXOSa. Diverse approaches will be used to conduct these studies including molecular biology, biochemistry, cell biology, murine models for tumorigenicity and a murine model for Bcr-Abl-induced leukemia. Chronic Myelogenous Leukemia (CML) is a blood cancer caused by the Bcr-Abl oncoprotein. Although the recently approved drug imatinib (IM) inhibits Bcr-Abl and is an effective CML treatment, the emergence of cancer cells resistant to IM mandates further research focusing on how Bcr-Abl causes evasion of cell suicide. FOXOSa, a major regulator of cell suicide, is suppressed by Bcr-Abl in CML. This proposal will seek to determine how FOXOSa is regulated by Bcr-Abl and if restoration of its activity will lead to CML regression. This study could potentially reveal novel therapeutic uses for FOXOSa in treating leukemia.
| Singh, Amrik; Plati, Jessica; Khosravi-Far, Roya (2011) Harnessing the tumor suppressor function of FOXO as an alternative therapeutic approach in cancer. Curr Drug Targets 12:1311-21 |
| Singh, Amrik; Ye, Min; Bucur, Octavian et al. (2010) Protein phosphatase 2A reactivates FOXO3a through a dynamic interplay with 14-3-3 and AKT. Mol Biol Cell 21:1140-52 |
