Rapamycin-sensitive induction of eukaryotic initiation factor 4F in regenerating mouse liver

Goggin, Melissa; Nelsen, Christopher J.; Kimball, Scot R.; Jefferson, Leonard S.; Morley, Simon; Albrecht, Jeffrey H.

doi:10.1002/hep.20338

Cited by 33 publications

(35 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, inhibition of TOR with rapamycin has been shown to prevent cyclin D1 expression at the level of protein but not mRNA in a number of models (including hepatocytes) by decreasing the translation of this protein (26,45,54). Similar to previous results in transgenic mice (15), treatment with rapamycin only partially diminished Akt-mediated growth.…”

Section: Discussionsupporting

confidence: 60%

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

Mullany

Nelsen

Hanse

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 60%

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

Mullany

Nelsen

Hanse

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Finally, mTORC1 promotes assembly of the eIF-4F complex, which mediates translation initiation of genes like Ccnd1 (24,26). In fact, mTORC1 has been shown to be needed for eIF-4F assembly and cyclin D1 translation in hepatocytes after 2/3 PH (27,28). Further considering that Akt1 activation is critical for the early phase of liver regeneration (29), we hypothesized that miR-21 facilitates rapid cyclin D1 translation in liver regeneration by relieving Akt1, and thus mTORC1, from inhibition by Rhob.…”

Section: Ref 4)mentioning

confidence: 99%

A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration

et al. 2012

View full text Add to dashboard Cite

MicroRNA-21 (miR-21) is thought to be an oncomir because it promotes cancer cell proliferation, migration, and survival. miR-21 is also expressed in normal cells, but its physiological role is poorly understood. Recently, it has been found that miR-21 expression is rapidly induced in rodent hepatocytes during liver regeneration after two-thirds partial hepatectomy (2/3 PH). Here, we investigated the function of miR-21 in regenerating mouse hepatocytes by inhibiting it with an antisense oligonucleotide. To maintain normal hepatocyte viability and function, we antagonized the miR-21 surge induced by 2/3 PH while preserving baseline expression. We found that knockdown of miR-21 impaired progression of hepatocytes into S phase of the cell cycle, mainly through a decrease in levels of cyclin D1 protein, but not Ccnd1 mRNA. Mechanistically, we discovered that increased miR-21 expression facilitated cyclin D1 translation in the early phase of liver regeneration by relieving Akt1/mTOR complex 1 signaling (and thus eIF-4F-mediated translation initiation) from suppression by Rhob. Our findings reveal that miR-21 enables rapid hepatocyte proliferation during liver regeneration by accelerating cyclin D1 translation.

show abstract

“…3). 30 Although the abundance of eIF4G can also rise during the transition from quiescence to cell cycle transit, 33 mechanisms regulating the levels of eIF4G expression remain to be elucidated.…”

Section: Translation Initiation Apparatusmentioning

confidence: 99%

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

Polunovsky¹,

Bitterman²

2006

RNA Biology

View full text Add to dashboard Cite

Rapamycin-sensitive induction of eukaryotic initiation factor 4F in regenerating mouse liver

Cited by 33 publications

References 42 publications

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

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

A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

Contact Info

Product

Resources

About