Abstract

Although a strong association between ras activation and human carcinogenesis has been established, both the mechanism of oncogenic ras transformation and its contribution to the malignant process remain to be determined. The overall goal of the proposed research is the identification of the structural and biochemical properties of the ras proteins that are important for neoplastic transformation. The interaction between ras and other cellular components that may regulate ras biological activity will also be emphasized. The general approach will entail the generation of structural and functional mutants of the human ras proteins. Chimeric proteins will also be constructed between H-ras and ras-related proteins. These ras-related proteins will include the recently identified Krev-1 protein, which suppresses oncogenic ras transforming activity. The biological activities of these mutant ras proteins will be characterized by a variety of in vitro biological assays. Additional in vitro cell transformation systems will also be established to address the involvement of oncogenic ras in the transformation of cells of epithelial origin. Overall, these approaches should generate useful information for identifying the properties of the oncogenic ras that are responsible for the malignant transformation and altered differentiation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042978-08
Application #
2091042
Study Section
Pathology B Study Section (PTHB)
Project Start
1986-07-01
Project End
1994-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Waters, Andrew M; Der, Channing J (2018) KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med 8:
Vaseva, Angelina V; Blake, Devon R; Gilbert, Thomas S K et al. (2018) KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism. Cancer Cell 34:807-822.e7
Papke, Bjoern; Der, Channing J (2017) Drugging RAS: Know the enemy. Science 355:1158-1163
Waters, Andrew M; Ozkan-Dagliyan, Irem; Vaseva, Angelina V et al. (2017) Evaluation of the selectivity and sensitivity of isoform- and mutation-specific RAS antibodies. Sci Signal 10:
Yin, Guowei; Kistler, Samantha; George, Samuel D et al. (2017) A KRAS GTPase K104Q Mutant Retains Downstream Signaling by Offsetting Defects in Regulation. J Biol Chem 292:4446-4456
Justilien, Verline; Ali, Syed A; Jamieson, Lee et al. (2017) Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma. Cancer Cell 31:256-269
Zhou, Bingying; Der, Channing J; Cox, Adrienne D (2016) The role of wild type RAS isoforms in cancer. Semin Cell Dev Biol 58:60-9
Lawson, Campbell D; Fan, Cheng; Mitin, Natalia et al. (2016) Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase-Activating Proteins in Basal-like Breast Cancers. Cancer Res 76:3826-37
Gentry, Leanna R; Karginov, Andrei V; Hahn, Klaus M et al. (2016) Characterization of an Engineered Src Kinase to Study Src Signaling and Biology. Methods Mol Biol 1360:157-67
Zhou, Bingying; Ritt, Daniel A; Morrison, Deborah K et al. (2016) Protein Kinase CK2? Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2? Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma. J Biol Chem 291:17804-15

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