Unique impact of RB loss on hepatic proliferation: Tumorigenic stresses uncover distinct pathways of cell cycle control

Christopher A. Reed, Christopher N. Mayhew, A. Kathleen McClendon, Erik S. Knudsen

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The retinoblastoma (RB) tumor suppressor pathway is disrupted at high frequency in hepatocellular carcinoma. However, the mechanisms through which RB modulates physiological responses in the liver remain poorly defined. Despite the well established role of RB in cell cycle control, the deletion of RB had no impact on the kinetics of cell cycle entry or the restoration of quiescence during the course of liver regeneration. Although these findings indicated compensatory effects from the RB-related proteins p107 and p130, even the dual deletion of RB with p107 or p130 failed to deregulate hepatic proliferation. Furthermore, although these findings suggested a modest role for the RB-pathway in the context of proliferative control, RB loss had striking effects on response to the genotoxic hepatocarcinogen diethylnitrosamine. With diethylnitrosamine, RB deletion resulted in inappropriate cell cycle entry that facilitated secondary genetic damage and further uncoupling of DNA replication with mitotic entry. Analysis of the mechanism underlying the differential impact of RB status on liver biology revealed that, while liver regeneration is associated with the conventional induction of cyclin D1 expression, the RB-dependent cell cycle entry, occurring with diethylnitrosamine treatment, was independent of cyclin D1 levels and associated with the specific induction of E2F1. Combined, these studies demonstrate that RB loss has disparate effects on the response to unique tumorigenic stresses, which is reflective of distinct mechanisms of cell cycle entry.

Original languageEnglish (US)
Pages (from-to)1089-1096
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number2
DOIs
StatePublished - 2010

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Retinoblastoma
Cell Cycle Checkpoints
Diethylnitrosamine
Liver
Cells
Cyclin D1
Cell Cycle
Liver Regeneration
Restoration
Tumors
Kinetics
Retinoblastoma Protein
DNA
DNA Replication
Proteins
Hepatocellular Carcinoma

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Unique impact of RB loss on hepatic proliferation : Tumorigenic stresses uncover distinct pathways of cell cycle control. / Reed, Christopher A.; Mayhew, Christopher N.; McClendon, A. Kathleen; Knudsen, Erik S.

In: Journal of Biological Chemistry, Vol. 285, No. 2, 2010, p. 1089-1096.

Research output: Contribution to journalArticle

Reed, Christopher A. ; Mayhew, Christopher N. ; McClendon, A. Kathleen ; Knudsen, Erik S. / Unique impact of RB loss on hepatic proliferation : Tumorigenic stresses uncover distinct pathways of cell cycle control. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 2. pp. 1089-1096.
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