Inhibition of cell growth by TGF beta 1 is associated with inhibition of B-myb and cyclin A in both BALB/MK and Mv1Lu cells.
The concept of positive and negative regulation of normal cellular growth by diffusible factors is well illustrated by the effects of epidermal growth factor and transforming growth factor beta 1 (TGF beta 1) on mouse keratinocytes (MK) and mink lung epithelial cells (Mv1Lu). MK and Mv1Lu are nontransformed cell lines that reversibly arrest at a point in late G1 in response to TGF beta 1. Previously, we have shown that expression of the protooncogene c-myc is induced upon epidermal growth factor stimulation of quiescent MK and Mv1Lu cells and that transcriptional suppression of c-myc by TGF beta 1 treatment is important in the TGF beta 1 growth inhibition pathway. Using epidermal growth factor-stimulated synchronized MK and Mv1Lu cells, we have investigated the mRNA expression of a large number of growth factor-inducible genes that are critical regulators of growth in G1 and at the G1/S transition. These genes, often found to be dysregulated in cancer, include transcription factors as well as cyclins and their associated kinases, that promote growth, and tumor suppressor genes, that inhibit growth. As reported here, TGF beta 1 significantly inhibited mRNA expression of B-myb and cyclin A in both cell lines, suggesting that these may be important common downstream targets in the growth inhibition pathway. In contrast, the expression patterns of cyclins D1 and D2 and the transcription factors E2F1 and E2F2 were unaffected in MK cells treated with TGF beta 1 but were significantly inhibited in TGF beta 1-treated Mv1Lu cells. We cite the evidence suggesting that the inhibition of B-myb and cyclin A may contribute to the late G1 arrest caused by TGF beta 1 and that these events may be linked through the actions of the product of the retinoblastoma susceptibility gene (Rb) or an Rb family member.
Satterwhite
D J
DJ
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Aakre
M E
ME
Gorska
A E
AE
Moses
H L
HL
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D019938:Cyclin D1; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D008168:Lung / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008907:Mink; D008934:Mitogens / Q000494:pharmacology; D015513:Oncogene Proteins / Q000235:genetics; D009857:Oncogenes; D012333:RNA, Messenger / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D008934:Mitogens; D015513:Oncogene Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019938:Cyclin D1