Ha-ras and v-raf oncogenes, but not int-2 and c-myc, interfere with the lactogenic hormone dependent activation of the mammary gland specific transcription factor.
beta-Casein milk protein expression is regulated synergistically by the lactogenic hormones dexamethasone, insulin, and prolactin. This regulation has been observed in vivo and in the mammary epithelial cell line HC11. An important mediator of hormone action on beta-casein gene transcription is the mammary gland specific transcription factor MGF. Epidermal growth factor is a potent growth promoter for HC11 cells and causes a state of predifferentiation in confluent HC11 cells. Epidermal growth factor receptor activation, however, antagonizes the effects of the lactogenic hormones on MGF activation and beta-casein gene transcription during the induction of predifferentiated cells. We examined the effects of two downstream components of the epidermal growth factor receptor mitogenic signaling pathway on MGF and beta-casein promoter activity. Constitutively activated Ha-ras or v-raf oncogenes were introduced into HC11 cells. HC11 cell lines transfected with Ha-ras or v-raf oncogenes assumed transformed properties and were blocked in the lactogenic induction of MGF and beta-casein gene transcription. This indicates that the same components instrumental in the mitogenic pathway are also involved in the block of differentiation specific gene expression in HC11 cells. This block is not due to the transformed state of the HC11 cells. Introduction and high expression of the int-2 gene, a member of the fibroblast growth factor gene family, does not interfere with MGF and beta-casein induction. Overexpression of the c-myc gene, causing mammary epithelial cell transformation, also does not suppress MGF activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Happ
B
B
Friedrich Miescher Institute, Basel, Switzerland.
Hynes
N E
NE
Groner
B
B
D000818:Animals; D002364:Caseins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D003907:Dexamethasone / Q000037:antagonists & inhibitors*; D066246:ErbB Receptors / Q000502:physiology; D005768:Gastrointestinal Hormones / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016259:Genes, myc / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000166:cytology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes / Q000235:genetics*; D012680:Sensitivity and Specificity; D014157:Transcription Factors / Q000502:physiology*
D002364:Caseins; D005768:Gastrointestinal Hormones; D014157:Transcription Factors; D003907:Dexamethasone; D066246:ErbB Receptors