UCSF

ABSTRACT

Using switchable mouse models to assess the

therapeutic potential of MdmX and E2F3

by

Daniel Garcia

Diverse as tumors are, they share some common features that are hallmarks of cancer. Two of these hallmarks are the evasion of tumor surveillance mechanisms and deregulated proliferation. Aiming to address these problems, we have used novel switchable mouse models to test the therapeutic potential of MdmX and E2F3, two genes directly involved in allowing tumor cells to evade tumor suppression and to proliferate, respectively.

MdmX is a critical negative regulator of p53 whose over-expression in many cancers is thought to block p53 tumor suppressor function. Consequently, inhibiting MdmX has emerged as an intriguing approach to restoring p53 function in established cancers. However, MdmX-deficient mice exhibit p53-dependent death early in embryogenesis, which has precluded elucidation of the consequences of systemic MdmX inhibition. To determine directly the effects of systemic MdmX inhibition in normal adult tissues and in tumors, we crossed mdmX-/- mice into the p53ERTAM knock-in background to obtain adult MdmX-null mice in which p53 function can be restored. p53 became active when transiently restored in these mice, but the effects of this activity were non-lethal and reversible. Moreover, absence of MdmX enhanced p53 restoration therapy in a mouse model of lymphoma. Hence, systemic inhibition of MdmX is a feasible therapeutic strategy for restoring p53 function in tumors that retain wild type p53.

The E2F family of transcription factors plays a key role in a number of cellular processes, including cellular proliferation and tumorigenesis. E2Fs are deregulated in the vast majority of cancer and appear to be essential conduits for upstream oncogenic lesions. Recent genetic studies in mice have established E2F3 as the most essential activating E2F for cellular proliferation and embryonic viability. However, the embryonic lethality of E2F3-null mice has prevented the study of the contribution of E2F3 to tumor proliferation and the assessment of E2F3 inhibition as a therapeutic avenue. To directly study E2F3 biology in adult tissues and tumors, we established a novel tet-repressor system that allows control of endogenous e2f3 expression in adult mice.