Transforming growth factor beta 1 regulation of c-myc expression, pRB phosphorylation, and cell cycle progression in keratinocytes.
Transforming growth factor beta 1 (TGF-beta 1) is a potent inhibitor of cellular proliferation in a variety of cell types, including skin keratinocytes. TGF-beta 1 suppression of c-myc transcription has been implicated in the mechanism of TGF-beta 1 inhibition of keratinocytes, and evidence suggests that the protein product of the retinoblastoma gene (pRB) is a necessary component in this pathway. Following growth factor stimulation of quiescent keratinocytes, TGF-beta 1 can inhibit cell cycle progression into S phase at any point prior to the G1-S transition but does not inhibit progression through the S phase of the cell cycle. Since pRB is hypophosphorylated during G1 and hyperphosphorylated during S and G2, the G1-S-specific phosphorylation of pRB becomes an attractive target for the growth-inhibitory activities of TGF-beta 1. However, in TGF-beta 1-treated primary human keratinocytes and in a series of human papilloma virus and SV40 immortalized human keratinocyte cell lines, the phosphorylation status of pRB strictly correlated with cell growth. No evidence was found for a direct effect of TGF-beta 1 on the phosphorylation state of pRB in these cells. It was further demonstrated that synthesis of c-myc protein can be rapidly inhibited by TGF-beta 1 addition throughout G1 and S phases, indicating that the phosphorylation state of pRB, at least as it varies during the cell cycle, does not alter the ability of TGF-beta 1 to suppress c-myc expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Münger
K
K
Laboratory of Tumor Virus Biology, National Cancer Institute, Bethesda, Maryland 20892.
Pietenpol
J A
JA
Pittelkow
M R
MR
Holt
J T
JT
Moses
H L
HL
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D016259:Genes, myc / Q000187:drug effects*; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta