Abstract

In the US., there are over one million new cancer cases each year which result in approximately one-half million deaths. In the near future more money will be expended on cancer treatment than any other disease. The long-range goals of the proposed studies are to increase our understanding of hematopoietic cell growth and malignant transformation to create novel therapies for the treatment of neoplasia. The central theme of this proposal is to understand how the aberrant activation of the Raf kinases can result in the abrogation of cytokine-dependency and the prevention of apoptosis in hematopoietic cell growth and malignant transformation to create novel therapies for the treatment of neoplasia. The abilities of conditionally active Raf kinases, which were generated by the fusion of the activated RAF (_Raf) alleles with the estrogen-receptor (ER) hormone binding domain (_Raf:ER), to abrogate the cytokine-dependency of hematopoietic cells were determined. Two types of cells were recovered, those which proliferated in response to deregulated _Raf:ER activity (estradiol-responsive) and those which did not (estradiol-non-responsive). The following specific aims were developed to understand how deregulated Raf kinase activity can abrogate cytokine-dependency:
Aim 1. To determine whether the signal transduction pathways in estradiol-responsive and estradiol-non-responsive _Raf:ER clones are biochemically different.
Aim 2. To determine the basis responsible for the differential abilities of the A-Raf, B-Raf and Raf-1 oncoproteins to abrogate the cytokine-dependency and Aim 3. To determine whether the abrogation of cytokine-dependency by the Raf oncoprotein is indirect and requires the activation of additional genes. Deregulation of cytokine-dependency and apoptosis have been implicated in the etiology of many different types of cancer and autoimmune diseases as well as neurodegenerative diseases and AIDS. An understanding of how these signal transduction and apoptotic pathways impinge upon one another will further our comprehension of the consequences of abnormal oncogene activation and tumor progression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA051025-07
Application #
6124598
Study Section
Pathology B Study Section (PTHB)
Program Officer
Finerty, John F
Project Start
1992-07-01
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
7
Fiscal Year
2000
Total Cost
$178,059
Indirect Cost

  Institution

Name
East Carolina University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Greenville
State
NC
Country
United States
Zip Code
27858

  Publications

Lehmann, Brian D; Paine, Matthew S; Brooks, Adam M et al. (2008) Senescence-associated exosome release from human prostate cancer cells. Cancer Res 68:7864-71
Franklin, Richard A; McCubrey, James A (2007) Polyphenols in breast cancer treatment. Cancer Biol Ther 6:62-3
McCubrey, James A; Franklin, Richard A (2006) Reactive oxygen intermediates and signaling through kinase pathways. Antioxid Redox Signal 8:1745-8
Franklin, Richard A; Rodriguez-Mora, Oswaldo G; Lahair, Michelle M et al. (2006) Activation of the calcium/calmodulin-dependent protein kinases as a consequence of oxidative stress. Antioxid Redox Signal 8:1807-17
Lahair, Michelle M; Howe, Christopher J; Rodriguez-Mora, Oswaldo et al. (2006) Molecular pathways leading to oxidative stress-induced phosphorylation of Akt. Antioxid Redox Signal 8:1749-56
McCubrey, James A; Lahair, Michelle M; Franklin, Richard A (2006) Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal 8:1775-89
Rodriguez-Mora, Oswaldo G; Lahair, Michelle M; Evans, Mark J et al. (2006) Inhibition of the CaM-kinases augments cell death in response to oxygen radicals and oxygen radical inducing cancer therapies in MCF-7 human breast cancer cells. Cancer Biol Ther 5:1022-30
McCubrey, James A; Lahair, Michelle M; Franklin, Richard A (2006) OSU-03012 in the treatment of glioblastoma. Mol Pharmacol 70:437-9
Konopleva, Marina; Shi, Yuexi; Steelman, Linda S et al. (2005) Development of a conditional in vivo model to evaluate the efficacy of small molecule inhibitors for the treatment of Raf-transformed hematopoietic cells. Cancer Res 65:9962-70
Rodriguez-Mora, Oswaldo G; LaHair, Michelle M; McCubrey, James A et al. (2005) Calcium/calmodulin-dependent kinase I and calcium/calmodulin-dependent kinase kinase participate in the control of cell cycle progression in MCF-7 human breast cancer cells. Cancer Res 65:5408-16

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