Understanding how the p53 tumor suppressor protein works to prevent oncogenesis is a subject of widespread interest. It is equally imperative to elucidate how its negative regulators, Mdm2 and MdmX function to restrain p53. Such information can both inform design of inhibitors that release wild-type p53 from Mdm2 or MdmX in tumors, and reveal signaling pathways that regulate Mdm2 for therapeutic advantage. Several novel findings were made in the previous granting period that will be pursued. First, we discovered TAB1, a scaffolding protein that regulates TAK1 and p38?;binds to Mdm2 and inhibits its ability to degrade p53 and Mdm2. Cisplatin is unique among many chemotherapeutic agents in requiring Tab1 to promote p53-mediated cell death in an MdmX- and p38?-dependent manner. Second, we have identified a new hydrophobic region within the Mdm2 N-terminus that enables Mdm2 to interact with the p53 NES region. Two patients with an atypical form of Progeria, a rare but severe inherited disease that predisposes afflicted people to premature aging and early death, harbor mutations in Mdm2, one of which deletes the same hydrophobic Mdm2 N-terminal region. This is the first example of Mdm2 mutation in a human aging related disease. Third, although Mdm2 and MdmX are believed to inhibit the ability of p53 to activate transcription of its target genes, we discovered that MdmX is actually required for full induction of Mdm2 and Wip1 after various forms of DNA damage and ribosomal stress. Thus, we uncovered a new mode by which MdmX represses p53 by facilitating expression of two of its negative regulators. To pursue these findings 3 Specific Aims are proposed.
In Aim 1 we will determine how cisplatin regulates TAB1 and its interactions Mdm2. We will also examine how TAB1 regulates MdmX and cell death in cisplatin treated cells. The mode by which TAB1 regulates select p53 target genes will also be elucidated.
Aim 2 will explore further the role of Mdm2 in Progeria and aging. We will document possible aging-related changes in cells engineered to harbor Progeria related Mdm2 mutations including senescence, ROS genome instability and others. We will also assess gene expression changes in such cells and characterize the structure and biochemical properties of these mutant forms of Mdm2. The Mdm2-NES interaction will be examined in cells and we will investigate whether it is relevant to aging related characteristics.
In Aim 3 we will seek to gain a fuller picture of MdmX-regulated genes and determine genome-wide how MdmX interacts with chromatin. We will elucidate the mechanism by which MdmX increases Mdm2 and Wip1 expression, via increasing p53 binding to their promoters. Finally we will validate our findings in cells from MdmX null mice.
That p53 is a major tumor suppressor is indisputable and its negative regulators Mdm2 and MdmX are increasingly studied as sources of therapeutics that could treat cancer patients with wild-type p53. We have identified TAB1 as being critical for inducing p53 dependent cell death in cancer cells treated with cisplatin, a commonly used therapeutic agent, and our findings may illuminate why some patients become resistant to treatment with this agent. We will also study the roles of p53 and Mdm2 in a disease associated with premature aging and will determine how MdmX functions as a transcriptional regulator of select p53 target genes.
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