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Papers In Press, published online ahead of print December 28, 2001
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Corresponding Author: shieldsj{at}med.unc.edu
Activated Ras but not Raf can transform RIE-1 and other epithelial cells, indicating the critical importance of Raf-independent effector function in Ras transformation of epithelial cells. To elucidate the nature of these Raf-independent activities, we utilized representational difference analysis to identify genes aberrantly expressed by Ras through Raf-independent mechanisms in RIE-1 cells. We identified a total of 22 genes, both known and novel, whose expression was either activated (10) or abolished (12) by Ras but not Raf. The genes upregulated encode proteins involved in protein or DNA synthesis, regulation of protease activity or ligand binding while those genes downregulated encode actin cytoskeletal-, extracellular matrix-, and gap junction-associated proteins, as well as transmembrane receptor- or cytokine-like proteins. These results suggest that a key function of Raf-independent signaling involves deregulation of gene expression. We further characterized transgelin as a gene whose expression was abolished by Ras. Transgelin was identified previously as a protein whose expression was lost in virally-transformed cell lines. We show that this loss is regulated at the level of gene expression and that both Raf-dependent and Raf-independent pathways are required to cause Ras downregulation of transgelin in RIE-1 cells, whereas Raf alone is sufficient to cause its loss in NIH 3T3 fibroblasts. We also found that Ras-dependent as well as Ras-independent mechanisms can cause the downregulation of transgelin in human breast and colon carcinoma cells lines and patient-derived tumor samples. We conclude that loss of transgelin gene expression may be an important early event in tumor progression and a diagnostic marker for breast and colon cancer development.
J. Biol. Chem, 10.1074/jbc.M110086200
Submitted on October 18, 2001
Revised on December 21, 2001
Accepted on December 28, 2001
Loss Of transgelin In breast and colon tumors and In RIE-1 cells by Ras deregulation of fene expression through Raf-independent pathways
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