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Mapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth.

ABSTRACT: Mapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth.

PROVIDER: PRJNA1101565 | ENA |

REPOSITORIES: ENA

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Project description:Mueller2015 - Hepatocyte proliferation, T160 phosphorylation of CDK2 This model is described in the article: T160-phosphorylated CDK2 defines threshold for HGF-dependent proliferation in primary hepatocytes. Mueller S, Huard J, Waldow K, Huang X, D'Alessandro LA, Bohl S, Börner K, Grimm D, Klamt S, Klingmüller U, Schilling M. Mol. Syst. Biol. 2015; 11(3): 795 Abstract: Liver regeneration is a tightly controlled process mainly achieved by proliferation of usually quiescent hepatocytes. The specific molecular mechanisms ensuring cell division only in response to proliferative signals such as hepatocyte growth factor (HGF) are not fully understood. Here, we combined quantitative time-resolved analysis of primary mouse hepatocyte proliferation at the single cell and at the population level with mathematical modeling. We showed that numerous G1/S transition components are activated upon hepatocyte isolation whereas DNA replication only occurs upon additional HGF stimulation. In response to HGF, Cyclin:CDK complex formation was increased, p21 rather than p27 was regulated, and Rb expression was enhanced. Quantification of protein levels at the restriction point showed an excess of CDK2 over CDK4 and limiting amounts of the transcription factor E2F-1. Analysis with our mathematical model revealed that T160 phosphorylation of CDK2 correlated best with growth factor-dependent proliferation, which we validated experimentally on both the population and the single cell level. In conclusion, we identified CDK2 phosphorylation as a gate-keeping mechanism to maintain hepatocyte quiescence in the absence of HGF. This model is hosted on BioModels Database and identified by: BIOMD0000000568. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Mapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth.

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