Tob1 is a Constitutively Expressed Repressor of Liver Regeneration

How proliferative and inhibitory cell signals integrate to control liver regeneration remains poorly understood. A screen for antiproliferative factors repressed after liver injury identified Tob1, a member of the PC3/BTG1 family of mitoinhibitory molecules as a target for further evaluation. Tob1 protein decreases after 2/3 hepatectomy in mice secondary to post-transcriptional mechanisms. Deletion of Tob1 increases hepatocyte proliferation and accelerates restoration of liver mass after hepatectomy. Down-regulation of Tob1 is required for normal liver regeneration and Tob1 controls hepatocyte proliferation in a dose-dependent fashion. Tob1 associates directly with both Caf1 and the Cyclin/cdk complex to modulate kinase activity. In addition, Tob1 has significant effects on the transcription of critical cell cycle components, including E2F targets and genes involved in p53 signaling. These studies provide direct evidence that levels of an inhibitory factor control the rate of liver regeneration. Our data identify Tob1 as a crucial check-point molecule that acts by by modulating levels and activity of cell cycle proteins.

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