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

Abstract

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 Rafindependent 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 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.

A novel interplay between oncogenic PFTK1 protein kinase and tumor suppressor TAGLN2 in the control of liver cancer cell motility

“…TAGLN, also named the smooth muscle protein 22-a (SM22-a), is an actin stress fiber-associated protein (Assinder et al, 2009). It is frequently downregulated in breast, colon (Shields et al, 2002;Wulfkuhle et al, 2002) and prostate cancers (Yang et al, 2007), where a tumor suppressor function has been proposed. In colorectal cancer, negative TAGLN expression has further been reported to be an independent prognostic indicator for shorter patient's survival (Zhao et al, 2009), whereas a role in impeding metastasis was suggested in breast carcinoma (Xu et al, 2010).…”

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

“…Inactivation of PPP2R1B by downregulation, or mutation, has been demonstrated in B-cell chronic lymphocytic leukaemia, lung cancer and colon cancer (Wang et al 1998). TAGLN is an actin cross-linker protein involved in replicative senescence, and loss of this gene has also been demonstrated in breast and colon cancer (Shields et al 2002, Yang et al 2007). There are no reports of RDX, BTG4, PPP2R1B or TAGLN expression in ileal carcinoids, and the role of these tumour-suppressor genes in carcinoid tumour progression remains to be determined.…”

Transgelin as a suppressor is associated with poor prognosis in colorectal carcinoma patients

“…Among them, a remarkable decreased expression of transgelin, a 22 kDa protein also called SM22, WS3-10 and mouse p27, and found abundantly in smooth muscle cells, [9][10][11] was found in colorectal cancer specimens. Transgelin has been shown to bind to and colocalize with F-actin, indicating that it may be involved in cell differentiation by stabilizing the cytoskeleton through actin binding, 12,13 and diminished expression of this protein has been reported in a variety of cell types on transformation [14][15][16] as well as in several human cancers, including lung, renal, prostate and breast cancer. 14,[17][18][19] According our current knowledge, there are few reports on its role in progression of colorectal cancer.…”