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J. Biol. Chem., Vol. 277, Issue 12, 9790-9799, March 22, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/12/9790    most recent M110086200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shields, J. M. Articles by Der, C. J. Search for Related Content PubMed PubMed Citation Articles by Shields, J. M. Articles by Der, C. J. Social Bookmarking                      What's this?

Loss of Transgelin in Breast and Colon Tumors and in RIE-1 Cells by Ras Deregulation of Gene Expression through Raf-independent Pathways^*

Janiel M. Shields, Kelley Rogers-Graham, and Channing J. Der

From the Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295

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 up-regulated encode proteins involved in protein or DNA synthesis, regulation of protease activity, or ligand binding, whereas those genes down-regulated encode actin cytoskeletal-, extracellular matrix-, and gap junction-associated proteins, and 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 down-regulation 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 and Ras-independent mechanisms can cause the down-regulation 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.

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