Senescence is a form of stable proliferative arrest historically associated with the exhaustion of replicative potential of cells. Activated oncogenes, such as ras, can induce senescence prematurely in young cells. Recent studies demonstrate that like apoptosis, oncogene-induced senescence is a bona fide tumor suppressing mechanism in vivo, which needs to be compromised during cancer development. However, the signaling pathways responsible for this important anti-tumorigenic response are poorly understood. Studies from our lab indicate that the p38 MAPK and its downstream substrate kinase PRAK play a key role in oncogenic ras-induced senescence and tumor suppression both in vitro and in vivo, and that PRAK is likely to be a tumor suppressor protein. Studies from the last funding period demonstrated that a multifunctional acetyltransferase Tip60 is also essential for oncogenic ras-induced senescence. Further analyses revealed a novel posttranslational modification cascade involving p38, Tip60 and PRAK, which plays an essential role in oncogenic ras-induced senescence. Upon activation by ras, p38 induces the acetyltransferase activity of Tip60 through phosphorylation of Thr158;activated Tip60, which directly interacts with PRAK, in turn induces the protein kinase activity of PRAK through acetylation of K364 in a manner that depends on phosphorylation of both Tip60 and PRAK by p38. These posttranslational modifications are critical for the pro-senescent function of Tip60 and PRAK, respectively. In the current renewal application, we propose to investigate the mechanism by which Tip60-mediated acetylation induces the activity and function of PRAK (Aim 1), the regulation of a novel Tip60 substrate by the p38-Tip60 pathway (Aim 2), and a possible tumor-suppressing role of this novel posttranslational modification cascade in vivo (Aim 3).
In Aim 1, we will test a hypothesis that Tip60-mediated acetylation induces PRAK activity and function by enhancing p38 docking and/or by relieving intramolecular autoinhibition, 2 mechanisms that may not be mutually exclusive.
In Aim 2, we will analyze the regulation of a novel Tip60 substrate ATM, a key regulator of ras-induced DNA damage responses, by the p38-Tip60 circuit during ras-induced senescence. Finally in Aim 3, we will investigate the role of the p38-mediated Tip60-Thr158 phosphorylation in tumor suppression in vivo using Tip60-T158A mutant mice in the DMBA-induced mouse skin carcinogenesis model. These studies will likely reveal novel molecular mechanisms that regulate the activity and function of PRAK, and provide new insights into signaling pathways mediating senescence and tumor suppression. Investigation of the p38-Tip60-PRAK cascade in vivo may lead to the development of novel cancer therapies targeting components of the senescence pathway.

Public Health Relevance

Studies proposed in this application are designed to investigate the mechanism of oncogene-induced senescence, an important tumor suppressive cellular response that is disrupted during human cancer development. These studies focus on a protein kinase PRAK and an acetyltransferase Tip60, both of which are likely to be tumor suppressor proteins, and a protein kinase ATM that plays a key role in the maintenance of genome stability. Results from these studies will reveal mechanisms that regulate the activity and function of PRAK, and provide new insights into signaling pathways that mediate senescence and tumor suppression, and may lead to the development of novel cancer therapies targeting the senescence pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA131231-05A1
Application #
8759845
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Hildesheim, Jeffrey
Project Start
2007-12-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$426,375
Indirect Cost
$201,375
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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