Role of p19ARF in MYC inactivation induced senescence and sustained tumor regression and generation of inducible BMI1 transgenic model
- Alper Yetil.
- Aug. 2011.
- Physical description
- online resource (xii, 127 pages) : illustrations (some color)
- Yetil, Alper.
- Attardi, Laura. thesis advisor.
- Felsher, Dean (Dean Walton). thesis advisor (primary).
- Oro, Anthony, 1958- thesis advisor.
- Sweet-Cordero, Eric thesis advisor (primary).
- Stanford University. Program in Cancer Biology.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references (p. 121-126). 119 refs.
- MYC oncogene overexpression leads to rapid induction of tumors in animal models. We have previously shown that inactivation of MYC in tumors causes tumor regression. We identified senescence as a critical mechanism of MYC inactivation induced sustained tumor regression. This is the first time oncogene inactivation induced, in contrast to oncogene induced, senescence is reported. Here, we show that tumor suppressors p16INK4A, pRB and p19ARF are required for induction of senescence as well as sustained tumor regression. Either knockout of p53 or p19ARF accelerated MYC induced lymphomas and resulted in a dramatic increase in the incidence of tumor recurrence. Neither loss of p19ARF or p53 prevented proliferative arrest or apoptosis upon MYC inactivation. Loss of p19ARF, but not p53, was associated with a strong inhibition of senescence upon MYC inactivation. We conclude that p19ARF is essential for MYC inactivation to elicit sustained tumor regression through the induction of senescence. We also provide evidence that p19ARF mediates its effect on senescence in a p53 independent manner. We have uncovered that, in the absence of p19ARF, MYC inactivation in lymphomas leads to strong upregulation of NANOG, POU5F1, SOX2, GATA4, GATA6 and CCND1. Presence of either transgenic MYC or p19ARF represses the expression of these genes. Upregulation of self renewal associated genes NANOG, POU5F1 and SOX2 suggests that p19ARF null lymphomas may have expanded cancer stem cell fraction, which, in turn, could explain the propensity of p19ARF null lymphomas to reoccur. p16INK4A and p19ARF expression are regulated by BMI1. To study the role of BMI1 in cancer, senescence and stem cells, we generated a mouse model of conditional BMI1 overexpression. We present preliminary results in characterization of conditional BMI1 mouse. We compare tumors that are induced by MYC and by both MYC and BMI1. Mouse model of conditional BMI1 overexpression will be a useful tool in the study of cancer, senescence and stem cells.
- Publication date
- Submitted to Program in Cancer Biology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2011.