Post-transcriptional Regulation Of PML Function
Pier P Scaglioni
Internal Medicineuniversity Of Texas Sw Med Ctr/dallas
Grant 5K08CA112325-05 from National Cancer Institute, IRG: NCI
Abstract: 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
Keywords: carcinogenesis, mitogen activated protein kinase, myelogenous leukemia, posttranslational modification, protein degradation, tumor suppressor protein cellular pathology, fibroblast, nonsmall cell lung cancer, phosphorylation, protein structure function green fluorescent protein, immunoprecipitation, laboratory mouse, mass spectrometry, matrix assisted laser desorption ionization, western blotting
Project start date: 2005-08-08
Project end date: 2010-07-31
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Post-transcriptional Regulation Of PML Function
Pier P Scaglioni
University Of Texas Sw Med Ctr/dallas Dallas, Tx 753909105
Grant 5K08CA112325-04 from National Cancer Institute, IRG: NCI
Abstract: 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.
Keywords: carcinogenesis, mitogen activated protein kinase, myelogenous leukemia, posttranslational modification, protein degradation, tumor suppressor protein, cellular pathology, fibroblast, nonsmall cell lung cancer, phosphorylation, protein structure function, green fluorescent protein, immunoprecipitation, laboratory mouse, mass spectrometry, matrix assisted laser desorption ionization, western blotting
Project start date: 2005-08-08
Project end date: 2010-07-31
5K08CA112325-04 (2007): $133893
5K08CA112325-02 (2006): $133893
Grants awarded to Pier P Scaglioni
Post-transcriptional Regulation Of PML Function
Pier P Scaglioni
Internal Medicineuniversity Of Texas Sw Med Ctr/dallas
Grant 5K08CA112325-05 from National Cancer Institute, IRG: NCI
Abstract: 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
Keywords: carcinogenesis, mitogen activated protein kinase, myelogenous leukemia, posttranslational modification, protein degradation, tumor suppressor protein cellular pathology, fibroblast, nonsmall cell lung cancer, phosphorylation, protein structure function green fluorescent protein, immunoprecipitation, laboratory mouse, mass spectrometry, matrix assisted laser desorption ionization, western blotting
Project start date: 2005-08-08
Project end date: 2010-07-31
1K08CA112325-01A1 (2005): $133893