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Molecular and Cellular Biology, April 2002, p. 2304-2317, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2304-2317.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Opposing Roles of the Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Cascades in Ras-Mediated Downregulation of Tropomyosin

Janiel M. Shields,* Heena Mehta, Kevin Pruitt, and Channing J. Der*

Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Received 2 November 2001/ Returned for modification 10 December 2001/ Accepted 20 December 2001

We showed previously that activated Ras, but not Raf, causes transformation of RIE-1 epithelial cells, demonstrating the importance of Raf-independent pathways in mediating Ras transformation. To assess the mechanism by which Raf-independent effector signaling pathways contribute to Ras-mediated transformation, we recently utilized representational difference analysis to identify genes expressed in a deregulated fashion by activated Ras but not Raf. One gene identified in these analyses encodes for {alpha}-tropomyosin. Therefore, we evaluated the mechanism by which Ras causes the downregulation of tropomyosin expression. By using RIE-1 cells that harbor inducible expression of activated H-Ras(12V), we determined that the downregulation of tropomyosin expression correlated with the onset of morphological transformation. We found that the reversal of Ras transformation caused by inhibition of extracellular signal-regulated kinase activation corresponded to a restoration of tropomyosin expression. Inhibition of p38 activity in Raf-expressing RIE-1 cells caused both morphological transformation and loss of tropomyosin expression. Thus, a reduction in tropomyosin expression correlated strictly with morphological transformation of RIE-1 cells. However, forced overexpression of tropomyosin in Ras-transformed cells did not reverse morphological or growth transformation, a finding consistent with the possibility that multiple changes in gene expression contribute to Ras transformation. We also determined that tropomyosin expression was low in two human tumor cell lines, DLD-1 and HT1080, that harbor endogenous mutated alleles of ras, but high in transformation-impaired, derivative cell lines in which the mutant ras allele has been genetically deleted. Finally, treatment with azadeoxycytidine restored tropomyosin expression in Ras-transformed RIE-1, HT1080, and DLD-1 cells, suggesting a role for DNA methylation in downregulating tropomyosin expression.

* Corresponding author. Mailing address: University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, CB 7295, Chapel Hill, NC 27599-7295. Phone: (919) 962-1057. Fax: (919) 966-0162. E-mail for Janiel M. Shields: shieldsj{at}med.unc.edu. E-mail for Channing J. Der: cjder{at}med.unc.edu.

Molecular and Cellular Biology, April 2002, p. 2304-2317, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2304-2317.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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