Estrogen-induced proliferation in cultured hepatocytes involves cyclin D1, p21(Cip1) and p27(Kip1).
The purpose of this study was to establish if estrogen-induced hepatocyte proliferation in vitro involves the cell cycle regulators cyclin D1, p21(Cip1), and p27(Kip1). Male rat hepatocytes were cultured in presence of 17-beta-estradiol (E2) +/- ICI-182780, a pure estrogen antagonist, and [3H]-thymidine, as required. DNA synthesis as well as p21(Cip1), p27(Kip1), and cyclin D1mRNA and protein levels were evaluated at different times (12, 24, 36, and 48 hours) of incubation. E2-increased DNA synthesis was correlated with cyclin D1 and p21(Cip1) (mRNA and protein) variations that were reversed by the addition of ICI-182780. p27(Kip1) protein levels progressively increased regardless of the presence of E2 or ICI-182780. Our data confirm that estrogens' stimulatory effect is related to their ability to increase cyclin D1 levels. The increase of p21(Cip1) is probably related to the reentry of hepatocytes in the quiescent state. p27(Kip1) protein is not able to arrest hepatocyte proliferation.
Barone
M
M
Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
Ladisa
R
R
Di Leo
A
A
Spano
D
D
Francioso
D
D
Aglio
V
V
Amoruso
A
A
Francavilla
A
A
Iolascon
A
A
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D008297:Male; D023421:Models, Animal; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012680:Sensitivity and Specificity
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004967:Estrogens; D012333:RNA, Messenger; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27