Abstract

This multidisciplinary program focuses on the molecular mechanisms whereby oncoproteins, tyrosine kinase receptors and tumor suppressor genes regulate cell survival. The program has four projects. There is also a request for an administrative and a nucleic acids core component.The investigators intend to study: i) the mechanisms and the significance of enhanced MDM2 levels in BCR/ABL-expressing cells and BCR/ABL-dependent leukemogenesis, the mechanisms whereby BCR/ABL suppresses C/EBPalpha expression and the biological consequences of restoring C/EBPalpha expression in BCR/ABL cells; ii) the mechanisms whereby the IGF-1 receptor promotes the localization of IRS-1 in the nucleus, the regulation of IRS-1 expression and promoter activity by IGF-1R and STAT-3, and the role of IRS-1, Id2, pRb, and STAT-3 in IGF-1-mediated regulation of apoptosis, proliferation and differentiation; iii) the pro-apoptotic effects involved in tumor suppression by the Fhit gene and the role of Fhit loss of function in tumorigenesis; iv) the role of the newly identified mitochondrial serine proteinase, Omi, in caspase-dependent and caspase-independent apoptosis and the involvement of the ER-localized GSPT-1 protein in the ER stress-induced apoptosis. The long-term objective of this Program Project is to utilize this information as a molecular basis for devising more rational approaches to anti-cancer therapies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA078890-04A2
Application #
6708169
Study Section
Subcommittee G - Education (NCI)
Program Officer
Spalholz, Barbara A
Project Start
2000-06-01
Project End
2008-05-31
Budget Start
2003-07-10
Budget End
2004-05-31
Support Year
4
Fiscal Year
2003
Total Cost
$1,290,933
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107

  Publications

Zou, Yaqun; Zwolanek, Daniela; Izu, Yayoi et al. (2014) Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. Hum Mol Genet 23:2339-52
Lidonnici, Maria Rosa; Audia, Alessandra; Soliera, Angela Rachele et al. (2010) Expression of the transcriptional repressor Gfi-1 is regulated by C/EBP{alpha} and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells. Cancer Res 70:7949-59
Bellodi, Cristian; Lidonnici, Maria Rosa; Hamilton, Ashley et al. (2009) Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest 119:1109-23
Chen, Jia; Capozza, Franco; Wu, An et al. (2008) Regulation of insulin receptor substrate-1 expression levels by caveolin-1. J Cell Physiol 217:281-9
Fernandes-Alnemri, Teresa; Alnemri, Emad S (2008) Assembly, purification, and assay of the activity of the ASC pyroptosome. Methods Enzymol 442:251-70
Trapasso, Francesco; Pichiorri, Flavia; Gaspari, Marco et al. (2008) Fhit interaction with ferredoxin reductase triggers generation of reactive oxygen species and apoptosis of cancer cells. J Biol Chem 283:13736-44
Khan, F S; Fujioka, M; Datta, P et al. (2008) The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in Drosophila. Cell Death Differ 15:1073-83
Wu, A; Chen, J; Baserga, R (2008) Nuclear insulin receptor substrate-1 activates promoters of cell cycle progression genes. Oncogene 27:397-403
Yu, Je-Wook; Fernandes-Alnemri, Teresa; Datta, Pinaki et al. (2007) Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell 28:214-27
Shi, Bin; Sepp-Lorenzino, Laura; Prisco, Marco et al. (2007) Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. J Biol Chem 282:32582-90

Showing the most recent 10 out of 49 publications