Abstract

The ability of BCR/ABL oncoproteins to induce leukemic transformation of hematopoietic cells depends on their tyrosine kinase activity, which is essential for the recruitment and the activation of multiple pathways (i.e., MAPkinase, Jun Kinase, PI-3k) that transduce oncogenic signals. Some of these pathways are also required for the anti-apoptotic effect of BCR/ABL. The objective of this proposal is t to delineate mechanisms involved in the survival-promoting effect of BCR/ABL and to assess the contribution of anti-apoptotic pathways for the leukmogenic potential of BCR/ABL. To this purpose, we will investigate mechanisms whereby three anti-apoptotic pathways regulated by BCR/ABL (Akt and STAT5 activation, mitochondrial targeting of Raf-1) promote cell survival and contribute to leukemogenesis. These studies should lead to a better understanding of the role of anti-apoptotic mechanisms in BCR/ABL leukemogenesis and the potential development of anti-leukemia therapies interfering with BCR/ABL-regulated survival signals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA078890-02
Application #
6347379
Study Section
Subcommittee G - Education (NCI)
Project Start
2000-06-01
Project End
2001-05-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$210,505
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Type
DUNS #
061197161
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