Ras Activation, Mutation, and Research

This web page was produced as an assignment for an undergraduate course at Davidson College.

     The Ras protein is activated by converting GDP to GTP.  In order to exchange GDP for GTP a guanine-nucleotide-exchange factor (GEF) is required to facilitate the transformation* (Bourne et al., 1991)   However, regulating the GEF is a guanine-nucleotide-dissociation inhibitor (GDI) which  inhibits the replacement of GDP to GTP in the activation process.  In the deactivation period GTP is intrinsically converted to GDP by GTPase activating proteins (GAP), however this process is mediated by GDI as well (Boguski et al., 1993).  

      Several members in the Ras G protein family have been linked to oncogenesis ( Malumbres et al., 1981).  Studies suggest that H-, K-, and N- Ras may be tumorigenic because of the inability to delocalize the GTP.  Thus, a signal is continuously relayed to the nucleus thereby causing increased proliferation.  Trends have been found linking different Ras genes to different human tumors.  For instance, the K-Ras is preferentially activated in the colon and pancreas carcinomas, H-Ras is primarily located in the bladder and kidney carcinomas, and the N-Ras is usually found in myeloid and lymphoid disorders (Bos, 1989).


In the gene-knockout studies of Ras particular residues were eliminated in rats.  The residues 5-63, 77-92, 109-123, 139-165, and the carboxyl terminal sequences (Cys 186-A-X-COOH) are required for the function of Ras (Barbalid, M., 1987).

     Recent research in rats has found that the drug mirthramycin may selectively bind to and inhibit the increased transcriptional activity associated with the tumorigenic H-Ras.  Mirthamycin, binds a specific G-C DNA site and thus selectively inhibits traniscription (Campbell et al., 1994).


*The GEF is also referred to as the the guanine-nucleotide-releasing proteins (GNRP) or the guanine-nucleotide-releasing proteins (GNRP). 






Barbarcid, M.  1987.  Ras genes.  Annual Review of Biochemistry.  56: 779-891.
Boguski, S., and F. McCormick.  1993.  Proteins regulating Ras and its relatives.  Nature.  366:  643-654.
Bas, L.  1989.  Ras oncogenes in human cancer: a review.  Cancer Research.  49:  4682-4689.

Bourne, H., McCormick, F., and D. Sanders.  1990.  The GTPase superfamily: a conserved switch for diverse cell      functions.  Nature.  348:125-132.

Bourne, H., McCormick, F., and D. Sanders.  1990.  The GTPase superfamily: conserved structure and molecular mechanism.  349:  117-126. 

Campbell, N.  1996.  Biology. 4th ed.  New York:  Benjamin/Cummings Company.
Campbell, V., Davin, D., Thomas, T., Jones, D., Roesel, J., Mayfield, C., and D. Miller.  1994.  The G-C specific DNA binding drug, Mithramycin, selectively inhibits transcription of the C-MYC and C-HA-Ras genes in regenerating liver.  307(3):  167-172.
Janeway CA, Travers P, Walport M, Capra JD. Immunobiology: the Immune System in Health and Disease. 4th ed.  London:  Current Biology Publication; 1999. p 163-193.
Lewin, B.  Genes.  Genes.  6th ed.  New York:  Oxford University Press; 1997.  p 1070-1076.
Mosteller, R.  Home Page.  Ras Protein Backbone.  <http://www-hsc.usc.edu/~rmostell/>  Accessed 2000 Feb 23.
Pellicer, A. and M. Malumbres.  1998.  Ras pathwways to cell cycle control and cell transfromation.  Frontiers in Bioscience.  3:  887-912.
Protein Data Bank. Structure Explorer-1QRA.  <http://www.rcsb.org/pdb/pe/explorer/
>.  Accessed 2000 Mar 1.
Scheidig, A.,  Burmester C.,  & R.S.Goody.  99 Jun 12.  Signaling Protein. Structure of Ras in complex with GTP at 100K.  <http://www.ncbi.nlm.nih.gov:80/cgi-bin/Entrez/Structure/mmdbsrv?form=6&db=t&Dopt=s&uid=11635>.  Accessed 2000 Mar  1.

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This web site was created for an Immunology class.  Please direct correspondence to jodickens@davidson.edu.

Last Updated March 3, 1999

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