This proposal details a 5-year training program for the development of an academic career in cancer biology. The PI will be mentored by Dr. Pier Paolo Pandolfi, a leading cancer biologist who has trained numerous independent investigators. The program will be enhanced by the collaboration of Dr. C. Cordon-Cardo, Dr. W. Pao, Dr. P. Tempst and by the guidance of an Advisory Committee composed of prominent scientists. Memorial Sloan-Kettering Cancer Center will provide the environmental resources to promote the success of this career development award. Research will focus on the study of the post-transcriptional mechanisms controlling the tumor suppressive function of the promyelocytic leukemia gene (PML). Pandolfi's laboratory has demonstrated that PML function is inhibited by PML-RARa, the product of the t(15;17) of acute promyelocytic leukemia, and that PML plays a critical role in multiple tumor suppressive functions including induction of replicative senescence, a powerful response to cell stress. The laboratory has also shown that PML protein is lost in a large portion of human tumors. PML loss correlated with tumor stage and grade in prostate, breast and central nervous systems tumors. The PI has demonstrated that: 1. PML protein loss is caused by aberrant protein degradation mediated by the ubiquitin/ proteasome system, and 2. PML is a direct substrate of ERK1/2 and p38 MAPK, two mitogen-activated protein kinases (MAPK) that transduce mitogenic and stress signals respectively. ERK1/2 induces PML degradation while p38 MAPK induces PML stabilization and increased activity. These findings indicate that PML is a direct target of the MAPK pathway. The PI hypothesizes that the pathways leading to PML ubiquitinylation and phosphorylation are key regulators of its tumor suppressor activity. The PI will address these hypotheses with the following specific aims: 1. characterization of the mechanisms underlying aberrant PML protein degradation in oncogenesis; 2. characterization of the function of p38 MAPK mediated PML phosphorylation as it pertains to regulation of PML protein stability and activity; 3. study the tumor suppressive function of PML in mouse tumor models where oncogenic K-Ras is conditionally expressed in the lung and in mouse embryonic fibroblasts. The training program outlined in this proposal will launch the PI's independent research career.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08CA112325-03
Application #
7339972
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2005-08-08
Project End
2010-07-31
Budget Start
2007-02-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$105,999
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Konstantinidou, Georgia; Ramadori, Giorgio; Torti, Francesca et al. (2013) RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov 3:444-57
Rabellino, Andrea; Carter, Brandon; Konstantinidou, Georgia et al. (2012) The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer Res 72:2275-84
Scaglioni, Pier Paolo; Rabellino, Andrea; Yung, Thomas M et al. (2012) Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence. EMBO Mol Med 4:594-602
Naina, Harris V; Levitt, Daniel; Vusirikala, Madhuri et al. (2011) Successful treatment of relapsed and refractory extramedullary acute promyelocytic leukemia with tamibarotene. J Clin Oncol 29:e534-6
Scaglioni, Pier Paolo; Cai, Lu Fan; Majid, Samia M et al. (2011) Treatment with 5-azacytidine accelerates acute promyelocytic leukemia leukemogenesis in a transgenic mouse model. Genes Cancer 2:160-5
Konstantinidou, Georgia; Bey, Erik A; Rabellino, Andrea et al. (2009) Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations. Cancer Res 69:7644-52
Scaglioni, P P; Yung, T M; Choi, S et al. (2008) CK2 mediates phosphorylation and ubiquitin-mediated degradation of the PML tumor suppressor. Mol Cell Biochem 316:149-54
Scaglioni, Pier Paolo; Yung, Thomas M; Cai, Lu Fan et al. (2006) A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 126:269-83