Dataset Information

Mouse liver regeneration quantitative proteomics

ABSTRACT: The liver is the only organ in mammals, which fully regenerates after injury. To identify novel regulators of liver regeneration, we performed quantitative large-scale proteomics analysis of subcellular fractions from normal versus regenerating mouse liver. Proteins of the ubiquitin-proteasome pathway were rapidly regulated by partial hepatectomy, with the ubiquitin ligase Nedd4-1 being among the top hits. Knock-down of Nedd4-1 in hepatocytes in vivo through nanoparticle-mediated delivery of siRNA caused severe liver damage after partial hepatectomy and impaired regeneration, resulting in liver failure. Mechanistically, we demonstrate that Nedd4-1 is required for efficient activation of Erk1/2 signaling by receptor tyrosine kinases involved in liver regeneration through inhibition of receptor internalization, thus controlling a major pro-mitogenic and cytoprotective signaling pathway in the regenerating liver. These results highlight the power of large-scale proteomics to identify key players in liver regeneration and the importance of posttranslational regulation of growth factor signaling in this process.

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Ulrich auf dem Keller

LAB HEAD: Sabine Werner

PROVIDER: PXD004108 | Pride | 2017-09-13

REPOSITORIES: Pride

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Publications

Large-Scale Quantitative Proteomics Identifies the Ubiquitin Ligase Nedd4-1 as an Essential Regulator of Liver Regeneration.

Bachofner Marc M Speicher Tobias T Bogorad Roman L RL Muzumdar Sukalp S Derrer Carina P CP Hürlimann Fabrizio F Böhm Friederike F Nanni Paolo P Kockmann Tobias T Kachaylo Ekaterina E Meyer Michael M Padrissa-Altés Susagna S Graf Rolf R Anderson Daniel G DG Koteliansky Victor V Auf dem Keller Ulrich U Werner Sabine S

Developmental cell 20170907 6

The liver is the only organ in mammals that fully regenerates even after major injury. To identify orchestrators of this regenerative response, we performed quantitative large-scale proteomics analysis of cytoplasmic and nuclear fractions from normal versus regenerating mouse liver. Proteins of the ubiquitin-proteasome pathway were rapidly upregulated after two-third hepatectomy, with the ubiquitin ligase Nedd4-1 being a top hit. In vivo knockdown of Nedd4-1 in hepatocytes through nanoparticle-m ...[more]

PMID: 28890072

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Project description:Normal adult liver is uniquely capable of renewal; and repair after injury. Whether this response; represents simple hyperplasia of various liver elements; or requires recapitulation of the genetic program of; the developing liver is not known. To study these possibilities, we examined transcriptional programs of adult liver after partial hepatectomy and contrasted these with developing embryonic liver. Principal component analysis demonstrated that the time series of gene expression during liver regeneration does not segregate according to developmental transcription patterns. Gene ontology analysis revealed that liver restoration after hepatectomy and liver development differ dramatically with regard to transcription factors and chromatin structure modification. In contrast, the tissues are similar with regard to proliferationassociated genes. Consistent with these findings, realtime polymerase chain reaction showed transcription factors known to be important in liver development are not induced during liver regeneration. These three lines of evidence suggest that at a transcriptional level, restoration of liver mass after injury is best described as hepatocyte hyperplasia and not true regeneration. We speculate this novel pattern of gene expression may underlie the unique capacity of the liver to repair itself after injury. Experiment Overall Design: In order to elucidate the molecular similarities between regenerating and developing liver, we performed high-density microarray analysis using Affymetrix MG 430 2.0 chips for targets at 0, 1, 2, 6, 12, 18, 24, 30, 48, and 72 hours after partial hepatectomy and at 10.5, 11.5, 12.5, 13.5, 14.5, and 16.5 days post conception (dpc). Experiment Overall Design: Each experimental time point is represented by two separate samples, each consisting of at least 3 pooled tissues from different animals. For example, 6 hepatectomies were performed for the 1 hour post-hepatectomy time point. Time 0 is used as control.

			Action	DRS
	20110629_01_CytA1.raw	Raw
	20110629_01_CytA1_merged.mgf	Mgf
	20110629_02_CytA2.raw	Raw
	20110629_02_CytA2_merged.mgf	Mgf
	20110629_03_CytA3.raw	Raw