Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

• Published in: Oncogene Vol. 17; no. 16; pp. 2047 - 2057
• Main Authors: COBELLIS, G, MISSERO, C, DI LAURO, R
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 22-10-1998; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Cell activation; Cell Differentiation; Cell Division; Cell Line; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Ectopic expression; Enzyme Activation; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - metabolism; Fibroblasts; Fundamental and applied biological sciences. Psychology; Genetic transformation; Growth factors; GTP Phosphohydrolases - metabolism; GTP-Binding Proteins - metabolism; H-Ras protein; MAP kinase; MAP Kinase Kinase 1; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Molecular and cellular biology; Phenotypes; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - metabolism; rac GTP-Binding Proteins; Rac1 protein; Rats; Thyrocytes; Thyroid; Thyroid gland; Thyroid Gland - cytology; Thyroid Gland - metabolism; Tumors; Human; Cell proliferation; Signal transduction; Regulation(control); Cell line; Epithelial cell; Activation; Thyroid gland; Cell differentiation; Cell transformation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1202130

Activating point mutations in the Ras oncogene occur in a large number of human tumors, especially of epithelial origin. In thyroid follicular cells, ectopic expression of oncogenic H-Ras results in growth factor-independent proliferation, loss of differentiation and tumor formation in nude mice. In fibroblasts concomitant activation of the MAP kinase cascade and the small GTPase Rac-1 leads to full malignant transformation. We have tested the effects of these key downstream mediators of Ras in thyroid epithelial cells, by stably expressing either a constitutively active form of MEK-1 (MEK(deltaN3/S218E/S222D)), a constitutively active form of Rac-1 (Val12-Rac), or both. While the activation of one molecule or the other results in a weak phenotype, concomitant activation of both MEK-1 and Rac-1 in thyroid cells leads to growth factor-independent proliferation, morphological transformation and anchorage-independent growth. However, in contrast to Ras-transformed thyroid cells, the ones expressing the constitutively active forms of MEK-1 and Rac-1 maintain their differentiate phenotype and fail to form tumors when injected into nude mice. Thus, in thyroid epithelial cells, concomitant activation of MEK-1 and Rac-1 can reproduce only a subset of the Ras-induced effects and is not sufficient to cause full malignant transformation. Significantly, Ras-mediated increased proliferation and loss of differentiation can be dissociated in these cells.