Abstract
Cyclins and cyclin-associated cdc kinases are key regulators of oocyte maturation (Maller, J. L. (1990) in The Biology and Medicine of Signal Transduction (Nishizuka, Y., Endo, M., and Tanaka, C., eds) pp. 323-328, Raven Press, New York), yeast cell cycles (Nurse, P. (1990) Nature 344, 503-508), DNA replication in cell-free systems (D'Urso, F., Marraccino, R. L., Marshak, R. R., and Roberts, J. M. (1990) Science 250, 786-791), and amphibian cell proliferative transitions (Hunt, T. (1991) Nature 350, 462-463). The extent to which these regulatory molecules participate in the growth control of differentiated epithelial cells like hepatocytes is unknown. Therefore, we investigated the expression of "G1" (E, C, and D) and "G2/M" (A, B1, and B2) cyclin mRNAs, the relative levels of cyclin A- and B1-associated histone H1-kinase activity, and the appearance of cyclin-associated kinases (p32/p33cdk2 and p33/p34cdc2) in regenerating rat liver and in control tissues from sham hepatectomized rats. To do this, we exploited a battery of human cyclin cDNAs and cyclin antisera that recognize rat molecules. The results suggest an apparent sequence of regeneration-specific changes: 1) elevated and induced expression of cyclins E (2.1 kilobases (kb)) and C (4 kb), and D mRNAs (4 kb), within 12 h, respectively; 2) induction of cyclins A (3.4 and 1.8 kb), B1 (2.5 and 1.8 kb), and B2 (1.9 kb) mRNAs at 24 h; 3) induction of cyclin A- and B1-associated nuclear histone H1 kinase at 24 h; and 4) enhanced levels of PSTAIRE-containing proteins of Mr approximately 32-33 and 33-34 kDa in nuclear extracts from 24-h regenerating liver that co-immunoprecipitate with cyclin A and B1 antisera, respectively. These observations provide an intellectual framework that unifies the biology of hepatocyte mitogenesis, proto-oncogene expression, and the machinery of the cell cycle.
Highlights
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We investigated the expression of "GI" (E, C, and D) and "G2/Mn (A, B1, and B2) cyclin mRNAs, the relative levels of cyclin A- and B1-associated histone H1-kinase activity, and the appearance of cyclin-associated kinases ( p 3 2 / ~ 3 3 "a~n' d~ p33/p34cdc2i)n regeneratingrat liver blots, first or second hybridization probes were removed[15]; all blots were subjected to hybridization with a-tubulin cDNA [15]
Additional features of cyclin mRNA expression were notable during regeneration
Summary
Hepatocellular proliferation is controlled by polypeptides (Received for publication, November 4,1991). 323-328, Raven Press, New York), yeast cell cycles histone H1 kinase activation, might occur in normal proliferating hepatocytes. 1.8kb), andB2 (1.9 kb) mRNAs at 24h; 3) induction a 5:l ratio (v/w) of Buffer A (50 mM Tris-HC1, pH 7, 50 mM of cyclin A- and B1-associated nuclear histone H1 ki- [NH,],SO,, 0.1 mM EDTA, 0.1 mM EGTA, 0.5 mM dithiothreitol, 1 nase at 24 h; and 4) enhanced levels of PSTAIRE- mM phenylmethylsulfonyl fluoride (Sigma), and 1 pg/pl aprotinin, containing proteins of M, -32-33 and 33-34 kDa in nuclear extracts from 24-h regenerating liver thcaotimmunoprecipitate withcyclin A and B1 antisera, releupeptin, and pepstatin (Boehringer Mannheim) for 10 s at 2000 rpm
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