Loss of p21 Permits Carcinogenesis from Chronically Damaged Liver and Kidney Epithelial Cells despite Unchecked Apoptosis

Holger Willenbring, Amar Deep Sharma, Arndt Vogel, Andrew Y. Lee, Andreas Rothfuss, Zhongya Wang, Milton Finegold, Markus Grompe

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)59-67
Number of pages9
JournalCancer Cell
Volume14
Issue number1
DOIs
StatePublished - Jul 8 2008

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Carcinogenesis
Epithelial Cells
Apoptosis
Kidney
Liver
Hepatocytes
Hepatocellular Carcinoma
Tyrosinemias
Liver Regeneration
Poisons
Cell Cycle Checkpoints
DNA Damage
Cysts
Carcinoma
Mortality
Growth

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Loss of p21 Permits Carcinogenesis from Chronically Damaged Liver and Kidney Epithelial Cells despite Unchecked Apoptosis. / Willenbring, Holger; Sharma, Amar Deep; Vogel, Arndt; Lee, Andrew Y.; Rothfuss, Andreas; Wang, Zhongya; Finegold, Milton; Grompe, Markus.

In: Cancer Cell, Vol. 14, No. 1, 08.07.2008, p. 59-67.

Research output: Contribution to journalArticle

Willenbring, Holger ; Sharma, Amar Deep ; Vogel, Arndt ; Lee, Andrew Y. ; Rothfuss, Andreas ; Wang, Zhongya ; Finegold, Milton ; Grompe, Markus. / Loss of p21 Permits Carcinogenesis from Chronically Damaged Liver and Kidney Epithelial Cells despite Unchecked Apoptosis. In: Cancer Cell. 2008 ; Vol. 14, No. 1. pp. 59-67.
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