Loss of p21 permits carcinogenesis from chronically damaged liver and kidney epithelial cells despite unchecked apoptosis.
Accumulation of toxic metabolites in hereditary tyrosinemia type I (HT1) patients leads to chronic DNA damage and the highest risk for hepatocellular carcinomas (HCCs) of any human disease. Here we show that hepatocytes of HT1 mice exhibit a profound cell-cycle arrest that, despite concomitant apoptosis resistance, causes mortality from impaired liver regeneration. However, additional loss of p21 in HT1 mice restores the proliferative capabilities of hepatocytes and renal proximal tubular cells. This growth response compensates cell loss due to uninhibited apoptosis and enables animal survival but rapidly leads to HCCs, renal cysts, and renal carcinomas. Thus, p21's antiproliferative function is indispensable for the suppression of carcinogenesis from chronically injured liver and renal epithelial cells and cannot be compensated by apoptosis.
Willenbring
Holger
H
Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. willenbringh@stemcell.ucsf.edu
Sharma
Amar Deep
AD
Vogel
Arndt
A
Lee
Andrew Y
AY
Rothfuss
Andreas
A
Wang
Zhongya
Z
Finegold
Milton
M
Grompe
Markus
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003512:Cyclohexanones / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism; D052177:Kidney Diseases, Cystic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009579:Nitrobenzoates / Q000494:pharmacology; D020176:Tyrosinemias / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D006867:Hydrolases; C020156:fumarylacetoacetase; C077073:nitisinone