My laboratory utilizes molecular and genetic approaches to study fundamental biological processes relevant to development and cancer, employing a broad range of experimental approaches to model human diseases and analyze complex phenotypes. A focal point of our studies is the PI3K / PTEN / AKT / Forkhead signalling pathway that is a nexus for fundamental cellular processes including metabolism, growth, and survival, with critical roles at the organismal level in aging, reproduction, and cancer.
Genetic analysis of FoxO forkhead transcription factors: We study the mechanisms underlying the activation of ovarian follicles in mammals, a process that requires communication between germ cells and surrounding somatic cells, and that has repercussions for infertility, contraception, and menopause/premature ovarian failure. Ovarian follicle activation is an irreversible and precisely regulated process, and we have shown that the forkhead transcription factor FoxO3 (a direct target of the kinase AKT) is part of the trigger mechanism that results in follicle activation and is an essential negative regulator of this process; mice deficient for FoxO3 thus undergo global ovarian follicle activation soon after birth. We are now undertaking a molecular and genetic dissection of mechanisms regulating ovarian follicle activation, including the role of FoxO3 itself in this process.
Cancer Biology-genetic systems and translational studies: We study malignancies of the reproductive tract including endometrial/ovarian cancer, using genetic and genomic approaches to uncover important genetic alterations that drive tumor initiation and progression. Approaches include Cre / Lox-based conditional genetic systems to generate faithful murine models permitting study of the underlying biology of these tumors, such as host / tumor interactions, hormone dependence, and roles of DNA repair pathways / genetic instability in driving tumorigenesis. To complement these studies, we are carrying out translational studies on banked human tumor specimens useful for direct analyses of genetic changes, expression profiling, or other molecular signatures that can be correlated with clinical behavior and outcome.
RESEARCH INTERESTS
PI3K / PTEN / AKT / FoxO pathway
Ovarian function / Infertility / Premature Ovarian Failure
Cancer Biology and Model Systems
RECENT PUBLICATIONS
Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH*, Depinho RA* (corresponding authors), "FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell Homeostasis" Cell, 128:309-323, January 2007
Castrillon DH, Miao L, Kallipara R, Horner J and Depinho RA., "Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a" Science, 301:215-8, 2003
Castrillon DH, Quade BJ, Wang TY, Quigley C, and Crum CP., "The human VASA gene is specifically expressed in the germ cell lineage" PNAS, 97(17):9585-90, 2000
Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, and DePinho RA., "Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis" Nature, 413:86-91, 2001
You MJ, Castrillon DH, Bastian BC, O'Hagan RC, Bosenberg MW, Parsons R, Chin L, and DePinho RA., "Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice" PNAS, 99(3):1455-60, 2002
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