The Cdk inhibitor p21 is required for necrosis, but it inhibits apoptosis following toxin-induced liver injury.
Liver injury and repair were examined in wild type, p21Waf1/Cip1, and p27Kip1-deficient mice following carbon tetrachloride (CCl4) administration. In wild type liver, p21 expression is induced in a biphasic manner following injection of CCl4, with an early peak of p21 expression occurring in pericentral hepatocytes at 6 h, prior to evidence of injury, and a second peak succeeding regenerative proliferation. In contrast, p27 is present throughout the quiescent liver, but its expression decreases following CCl4 injection. Surprisingly, p21-deficient animals were resistant to CCl4-induced necrotic injury, indicating that rapid induction of p21 in pericentral hepatocytes following CCl4 injection contributes to subsequent necrosis. Expression of cytochrome P450 2E1, which plays an essential role in CCl4-induced necrotic injury, was not affected in p21-deficient mice. Although they had the least injury, p21-deficient mice had the highest levels of hepatic proliferation that correlated with increases in hyperphosphorylated retinoblastoma protein and Cyclin A gene expression. Increased replication in p21-deficient livers was counteracted by an increase in hepatocyte apoptosis as detected by caspase-3 activation. p21 plays distinct and opposing roles regulating hepatocyte survival during injury and subsequent repair, with early induction of p21 contributing to necrotic injury and later expression to cessation of proliferation and hepatocyte survival.
Kwon
Young Hye
YH
Department of Molecular Genetics, University of Illinois, Chicago, Illinois 60607, USA.
Jovanovic
Aleksandra
A
Serfas
Michael S
MS
Tyner
Angela L
AL
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D002455:Cell Division; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000502:physiology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000293:injuries* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D010766:Phosphorylation; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D000410:Alanine Transaminase; D020169:Caspases