PTEN is a tumor suppressor that is deregulated in a large number of human cancers to activate the oncogenic phosphoinositide-3 kinase (PI3K) pathway. Inactivation of PTEN leads to multiple phenotypes including cancer, changes in stem cell biology and alteration of fundamental processes such as proliferation and apoptosis. We have recently determined that the PI3K pathway activates the transcriptional repressor NFIL3/E4BP4. NFIL3 is over expressed in human breast cancers lacking PTEN. Moreover, over expression of NFIL3 is seen in multiple types of poor-prognosis cancer. We have shown that NFIL3 binds and recruits HDAC2 to promoters to deacetylate histones and silence genes and even represses a recently recognized pool of nuclear FOXO proteins at multiple FOXO target genes. Our findings have broad implications that suggest that NFIL3, which represses numerous non-FOXO targets, could mediate reprogramming of chromatin as a consequence of PTEN mutation. This application will use a combination of biochemistry, signal transduction, mouse genetics, and cancer cell biology to address the following goals 1) to understand the mechanism by which NFIL3 alters the epigenetic regulation of target genes, 2) to determine the contribution of NFIL3 to changes in gene expression and chromatin modification caused by genetic ablation of PTEN, 3) to demonstrate the contribution of NFIL3 to tumor and other phenotypes due to PTEN mutation in mice and cells, and 4) to define how NFIL3 is regulated by PTEN and its implication for PI3K- based cancer therapy.
Analysis of human tumors has shown that the PI3K pathway is one of the most frequently activated pathways in many forms of malignancy. Here we will define an important mechanism of PI3K regulation of NFIL3 that appears to be responsible for modulating chromatin in a PI3K- dependent manner. This work has important implications for cancer and stem cell biology.
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|Hopkins, Benjamin D; Parsons, Ramon E (2014) Molecular pathways: intercellular PTEN and the potential of PTEN restoration therapy. Clin Cancer Res 20:5379-83|
|Hopkins, Benjamin D; Hodakoski, Cindy; Barrows, Douglas et al. (2014) PTEN function: the long and the short of it. Trends Biochem Sci 39:183-90|
|Keniry, Megan; Pires, Maira M; Mense, Sarah et al. (2013) Survival factor NFIL3 restricts FOXO-induced gene expression in cancer. Genes Dev 27:916-27|
|Hopkins, Benjamin D; Fine, Barry; Steinbach, Nicole et al. (2013) A secreted PTEN phosphatase that enters cells to alter signaling and survival. Science 341:399-402|
|Shen-Li, Hong; Koujak, Susan; Szablocs, Matthias et al. (2010) Reduction of Pten dose leads to neoplastic development in multiple organs of Pten (shRNA) mice. Cancer Biol Ther 10:1194-200|
|Fine, Barry; Hodakoski, Cindy; Koujak, Susan et al. (2009) Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science 325:1261-5|
|Maurer, Matthew; Su, Tao; Saal, Lao H et al. (2009) 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res 69:6299-306|
|Szabolcs, Matthias; Keniry, Megan; Simpson, Laura et al. (2009) Irs2 inactivation suppresses tumor progression in Pten+/- mice. Am J Pathol 174:276-86|
|Horst, Basil; Gruvberger-Saal, Sofia K; Hopkins, Benjamin D et al. (2009) Gab2-mediated signaling promotes melanoma metastasis. Am J Pathol 174:1524-33|
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