Astrocytoma is the most common malignant brain tumor in humans and is currently incurable due to its diffusely infiltrative behavior. We have developed a mouse model of astrocytoma that recapitulates the infiltrative behavior of human astrocytoma. In this mouse model the tumor suppressor genes Nf1 and p53 are mutated. Because both NF1 and p53 are frequently mutated in sporadic glioblastoma (GBM), this mouse model is a powerful tool for understanding the biology of tumors associated with neurofibromatosis type 1, as well as sporadic anaplastic astrocytomas and glioblastomas. We are using this mouse model to examine the signal transduction pathways necessary for proliferation and migration of astrocytoma cells both in vivo and in vitro. An understanding of these mechanisms will lead to the development of new therapies for astrocytoma. During fiscal year 2013, we focused on the role of the transcription factor, Cdca7l, on cell proliferation and cell death. This gene is a candidate for the Arlm1 modifier we identified in Project 1, and has been shown by others to interact with the oncogene myc. Our current research shows that Cdca7l regulates G1/S in male cells, differently from female cells, by upregulating CyclinD1 and inhibiting p27. In addition, Cdca7l regulates Caspase 3 in male cells, promoting survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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Zemp, Franz J; McKenzie, Brienne A; Lun, Xueqing et al. (2013) Resistance to oncolytic myxoma virus therapy in nf1(-/-)/trp53(-/-) syngeneic mouse glioma models is independent of anti-viral type-I interferon. PLoS One 8:e65801
Amlin-Van Schaick, Jessica C; Kim, Sungjin; DiFabio, Christina et al. (2012) Arlm1 is a male-specific modifier of astrocytoma resistance on mouse Chr 12. Neuro Oncol 14:160-74
Gursel, Demirkan B; Connell-Albert, Yvette S; Tuskan, Robert G et al. (2011) Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies. Neuro Oncol 13:610-21
Walrath, Jessica C; Hawes, Jessica J; Van Dyke, Terry et al. (2010) Genetically engineered mouse models in cancer research. Adv Cancer Res 106:113-64
Banerjee, Sutapa; Byrd, Jonathan N; Gianino, Scott M et al. (2010) The neurofibromatosis type 1 tumor suppressor controls cell growth by regulating signal transducer and activator of transcription-3 activity in vitro and in vivo. Cancer Res 70:1356-66
Reilly, Karlyne M (2009) Neurofibromatosis and lessons for the war on cancer. EMBO Mol Med 1:198-200
Reilly, Karlyne M; Rubin, Joshua B; Gilbertson, Richard J et al. (2008) Rethinking brain tumors: the fourth Mouse Models of Human Cancers Consortium nervous system tumors workshop. Cancer Res 68:5508-11
Reilly, Karlyne M; Van Dyke, Terry (2008) It takes a (dysfunctional) village to raise a tumor. Cell 135:408-10