Indiana University-Purdue University Indianapolis (IUPUI) / The transcription factor and tumor suppressor protein p53 critically regulates cell
survival or death in response to cellular stress. p53 can activate genes involved in a wide
variety of processes, including apoptosis, cell cycle arrest, angiogenesis, metabolism, and
senescence. Mutations in p53 are common in cancer and alter its interactions with other
proteins, but there are other mechanisms and posttranslational modifications that can alter
these interactions as well. In some tumors, such as renal cell carcinoma, p53 is commonly
inactive even though mutations to TP53 are rare. This suggests that there are other
biochemical mechanisms of inhibition, which we explore in this study.
Mutations in the DNA-binding domain of p53 result in conformational changes
that enable p53 to interact with and inhibit its family member p73, thereby promoting cell
survival instead of apoptosis. In contrast, it has been reported that wild-type p53 does not
bind to p73. We found that JNK-mediated phosphorylation of Thr81 in the proline-rich
domain (PRD) of p53 enabled wild-type p53 to form a complex with p73. The
dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target
genes such as PUMA and BAX, as well as the induction of apoptosis. In addition to the
apoptotic function of p53, the tumor suppressor also plays a major role in the inhibition
of angiogenesis.
Here we also report a new mechanism where the Mdm2 oncoprotein can
indirectly inactive p53 through the regulation of the tumor suppressor VHL. In response
to hypoxia, VHL can bind p53, which results in activation of several anti-angiogenic targets of p53 such as THBS1 and COL18A1. Mdm2 regulates the VHL-p53 interaction
by conjugating nedd8 to VHL within a region that is important for the VHL-p53
interaction, blocking the induction of anti-angiogenic genes and resulting in a
proangiogenic phenotype. Due to its positive regulation of major proangiogenic proteins
and its negative regulation of potent inhibitors of angiogenesis, we propose that the
oncoprotein Mdm2 is the angiogenic switch. These findings refine our understanding of
p53 interactions and activation, specifically for p53-p73 induced cell death and p53-VHL
inhibition of angiogenesis. / 2020-08-05
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/20224 |
| Date | 07 1900 |
| Creators | Wolf, Eric R. |
| Contributors | Mayo, Lindsey, Goebl, Mark, Ivan, Mircea, Mendonca, Marc, Wells, Clark |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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