 conditional knockout mice to determine the effects of c-Met dysfunction in hepatocytes on kinetics of liver regeneration. primary hepatocytes and partially restored expression levels of mitotic cell cycle regulators albeit to a lesser degree as compared to control cultures.In conclusion, our results assign a novel non-redundant function for HGF/c-Met signaling in regulation of G2/M gene expression program via maintaining a persistent Erk1/2 activation throughout liver regeneration

A Lindqvist

A Natarajan

BM Bolstad

C Birchmeier

C Boccaccio

C Fremin

C Postic

CG Huh

DA Thrower

Daekwan Seo

DP Bottaro

EC Roberts

Elizabeth A. Conner

G Fang

G Shiota

GF Vande Woude

GK Michalopoulos

H Goto

H Talarmin

Irene Oi Lin Ng

J Laoukili

J Li

J Quackenbush

JC Chambard

Jens U. Marquardt

Jesper B. Andersen

JH Wright

JS Lee

K Matsumoto

K Strimmer

LA Scheving

LO Murphy

M Bollen

M Borowiak

M Neuhauser

MJ Hendzel

ML Whitfield

N Fausto

N Larsson

PA Dumesic

Pal Kaposi-Novak

R Suryadinata

R Taub

S Meloche

S Paranjpe

S Ruchaud

Snorri S. Thorgeirsson

T Ito

T Yamamoto

Tsuyoshi Ishikawa

Valentina M. Factor

X Liu

Y Liao

Z Fu

PLoS ONE

English

PubMed

Factor Valentina M.

Seo Daekwan

Ishikawa Tsuyoshi

Kaposi-Novak Pal

Marquardt Jens U.

Andersen Jesper B.

Conner Elizabeth A.

Thorgeirsson Snorri S.

Public Library of Science (PLOS)

Loss of c-Met Disrupts Gene Expression Program Required for G2/M Progression during Liver Regeneration in Mice

Previous work has established that HGF/c-Met signaling plays a pivotal role in regulating the onset of S phase following partial hepatectomy (PH). In this study, we used Met(fl/fl);Alb-Cre(+/-) conditional knockout mice to determine the effects of c-Met dysfunction in hepatocytes on kinetics of liver regeneration.The priming events appeared to be intact in Met(fl/fl);Alb-Cre(+/-) livers. Up-regulation of stress response (MAFK, IKBZ, SOCS3) and early growth response (c-Myc, c-Jun, c-Fos, DUSP1 and 6) genes as assessed by RT-qPCR and/or microarray profiling was unchanged. This was consistent with an early induction of MAPK/Erk and STAT3. However, after a successful completion of the first round of DNA replication, c-Met deficient hepatocytes were blocked in early/mid G2 phase as shown by staining with phosphorylated form of histone H3. Furthermore, loss of c-Met in hepatocytes diminished the subsequent G1/S progression and delayed liver recovery after partial hepatectomy. Upstream signaling pathways involved in the blockage of G2/M transition included lack of persistent Erk1/2 activation and inability to up-regulate the levels of Cdk1, Plk1, Aurora A and B, and Mad2 along with a defective histone 3 phosphorylation and lack of chromatin condensation. Continuous supplementation with EGF in vitro increased proliferation of Met(fl/fl);Alb-Cre(+/-) primary hepatocytes and partially restored expression levels of mitotic cell cycle regulators albeit to a lesser degree as compared to control cultures.In conclusion, our results assign a novel non-redundant function for HGF/c-Met signaling in regulation of G2/M gene expression program via maintaining a persistent Erk1/2 activation throughout liver regeneration

Valentina M Factor

Jens U Marquardt

Jesper B Andersen

Elizabeth A Conner

Snorri S Thorgeirsson

Directory of Open Access Journals

Loss of c-Met disrupts gene expression program required for G2/M progression during liver regeneration in mice.

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2940888

Loss of c-Met Disrupts Gene Expression Program Required for G2/M Progression during Liver Regeneration in Mice

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Public Library of Science (PLOS)

Public Library of Science (PLOS)

Directory of Open Access Journals

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