Down-regulation of tropomyosin-2 expression in c-Jun-transformed rat fibroblasts involves induction of a MEK1-dependent autocrine loop.
Overexpression of the c-Jun transcription factor in rodent fibroblasts may result in cell transformation or in apoptosis. The mechanisms whereby c-Jun induces transformation are unknown. We show here that the expression of high-molecular weight tropomyosin-2 (TM-2) is down-regulated in c-jun-transformed FR3T3 rat fibroblasts. However, down-regulation did not seem to be a direct effect of c-Jun on TM-2 gene expression. Thus, TM down-regulation in c-jun-transformed cells was alleviated by inhibitors of Ras (BZA-5B) or MEK1 (PD98059). Furthermore, medium conditioned by c-jun-transformed cells induced TM-2 down-regulation in untransformed cells by a mechanism requiring MEK1. Consistent with a central role for the MEK/ERK, but not SEK/JNK, pathway for TM down-regulation, constitutively active mutants of Raf induced TM down-regulation, whereas constitutively active Rac did not. We also show that anchorage-independent growth of c-jun-transformed cells requires MEK1. These findings suggest that indirect induction of the MEK/ERK pathway is central to c-Jun-induced transformation of rat fibroblasts.
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute and Hospital, Stockholm, Sweden.
S
S
Ljungdahl
S
S
Linder
B
B
Franzén
B
B
Binétruy
G
G
Auer
M C
MC
Shoshan
D000818:Animals; D019898:Autocrine Communication; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D029721:Drosophila Proteins; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D027384:Oncogene Proteins v-raf; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology*; D051381:Rats; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology; D014335:Tropomyosin / Q000235:genetics*
D029721:Drosophila Proteins; D016755:Proto-Oncogene Proteins c-jun; D015682:Retroviridae Proteins, Oncogenic; C097163:Tm2 protein, Drosophila; C490773:Tpm1 protein, rat; D014335:Tropomyosin; D011505:Protein-Tyrosine Kinases; D027384:Oncogene Proteins v-raf; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases