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 Scopus citations

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 - Jan 19 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Unique impact of RB loss on hepatic proliferation: Tumorigenic stresses uncover distinct pathways of cell cycle control'. Together they form a unique fingerprint.

  • Cite this