Akt-mediated Liver Growth Promotes Induction of Cyclin E through a Novel Translational Mechanism and a p21-mediated Cell Cycle Arrest

Abstract

The control of hepatocyte growth is relevant to the processes of liver regeneration, development, metabolic homeostasis, and cancer. A key component of growth control is the protein kinase Akt, which acts downstream of mitogens and nutrients to affect protein translation and cell cycle progression. In this study, we found that transient transfection of activated Akt triggered a 3-4-fold increase in liver size within days but only minimal hepatocyte proliferation. Akt-induced liver growth was associated with marked up-regulation of cyclin E but not cyclin D1. Analysis of liver polyribosomes demonstrated that the post-transcriptional induction of cyclin E was associated with increased translational efficiency of this mRNA, suggesting that cell growth promotes expression of this protein through a translational mechanism that is distinct from the cyclin D-E2F pathway. Treatment of Akt-transfected mice with rapamycin only partially inhibited liver growth and did not prevent the induction of cyclin E protein, indicating that target of rapamycin activity is not necessary for this response. In the enlarged livers, cyclin E-Cdk2 complexes were present in high abundance but were inactive due to increased binding of p21 to these complexes. Akt transfection of p21 ؊/؊ mice promoted liver growth, activation of Cdk2, and enhanced hepatocyte proliferation. In conclusion, growth promotes cyclin E expression through a novel translational mechanism in the liver, suggesting a new link between cell growth and the cell cycle machinery. Furthermore, p21 suppresses proliferation in the overgrown livers and may play a role in preventing cell cycle progression in response to organ size homeostatic mechanisms.Although the terms are often used interchangeably, cell growth and proliferation reflect distinct processes. Cell growth refers to an increase in cell mass resulting from enhanced synthesis of proteins and other macromolecules, whereas proliferation refers to cell cycle progression resulting in increased cell number (1-6). In many cases, extracellular stimuli, such as mitogens, promote both growth and proliferation, so that subsequent generations of cells maintain normal size. However, cell growth can be induced in the absence of proliferation, depending on the stimulus and target cell. The intracellular pathways that regulate growth are incompletely characterized, but several key mediators have been identified (1-6). In particular, signaling through the phosphoinositide 3-kinase pathway appears to play an important role in growth regulation.A major downstream target of phosphoinositide 3-kinase is the serine/threonine protein kinase Akt (also known as protein kinase B), which regulates diverse processes, including glucose homeostasis, transcription, apoptosis, cell motility, angiogenesis, proliferation, and growth (7-10). Akt has been identified as an oncogene, and this kinase is frequently activated in malignant cells (11). Numerous studies have implicated Akt signaling as an important mediator of cell and organ growth. For exampl...

The Adventures of Sonic Hedgehog in Development and Repair. II. Sonic hedgehog and liver development, inflammation, and cancer

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Nrf2 Participates in Regulating Maternal Hepatic Adaptations to Pregnancy

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Hepatocellular alterations and dysregulation of oncogenic pathways in the liver of transgenic mice overexpressing growth hormone

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