Lovastatin inhibits prolactin-induced Nb2 cell mitogenesis and milk product synthesis in mouse mammary gland explants.
The p21ras protein has been shown to be active in many growth factor signaling systems, including that of prolactin (PRL). In our studies, the main objective was to examine further the involvement of ras in prolactin-stimulated mitogenic and metabolic processes. We used the farnesylation inhibitor lovastatin to block effectively ras-dependent signaling in Nb2 cells, a pre-T lymphoma cell line, and mammary gland explants derived from 12- to 14-day pregnant mice. Lovastatin completely inhibited PRL-induced Nb2 cell mitogenesis at 1 micron. In the mammary gland, lovastatin at 0.1 micron inhibited the PRL stimulation of lipid and lactose synthesis; at 2 microns, lovastatin abolished the PRL stimulation of casein production. When p21ras was immunoprecipitated from lovastatin (25 microns)-treated Nb2 cells and mammary gland explants, the unfarnesylated (inactive) form of ras was shown to be redistributed from the cell membrane to the cytosolic compartment of the cell. This suggests that the anchoring of ras to the cell membrane is essential for its action in prolactin signal transduction. Thus, in addition to the well-known active participation of ras in mitogenic growth factor signaling, the presence of functional ras also appears necessary for the PRL stimulation of specific metabolic processes involved in lactation.
Camarillo
I G
IG
Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Rillema
J A
JA
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D007785:Lactose / Q000096:biosynthesis; D008148:Lovastatin / Q000494:pharmacology*; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D011247:Pregnancy; D011388:Prolactin / Q000494:pharmacology*; D017368:Protein Prenylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*
D011388:Prolactin; D008148:Lovastatin; D016283:Proto-Oncogene Proteins p21(ras); D007785:Lactose