Adenoviral-mediated transfer of p53 or retinoblastoma protein blocks cell proliferation and induces apoptosis in culture-activated hepatic stellate cells

The principal cellular effectors of fibrosis in liver are hepatic stellate cells (HSC). In response to liver injury these quiescent cells undergo a phenotypic change to a myofibroblastic cell type, proliferate and secrete matrix components. Thus, removal of activated HSC should be beneficial for the...

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Veröffentlicht in:Journal of hepatology 2003-02, Vol.38 (2), p.169-178
Hauptverfasser: ABRISS, Bärbel, HOLLWEG, Günter, GRESSNER, Axel M, WEISKIRCHEN, Ralf
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container_issue 2
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container_title Journal of hepatology
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creator ABRISS, Bärbel
HOLLWEG, Günter
GRESSNER, Axel M
WEISKIRCHEN, Ralf
description The principal cellular effectors of fibrosis in liver are hepatic stellate cells (HSC). In response to liver injury these quiescent cells undergo a phenotypic change to a myofibroblastic cell type, proliferate and secrete matrix components. Thus, removal of activated HSC should be beneficial for the prognosis of hepatic fibrogenesis and preserve organ function. The purpose of this study was to investigate whether administration of adenoviruses constitutively expressing the p53 tumor suppressor or the retinoblastoma protein (pRb) is sufficient to induce cell arrest or apoptosis in culture-activated HSC. The expression of the transgenes was confirmed by Western blot analysis and immunohistochemistry. Both proteins were expressed mainly in the nucleus and their expression was associated with a marked inhibition of cell proliferation and induction of apoptosis as determined by measurement of phosphatidylserine exposed at the surface, proliferation assay, induction of the p21 cyclin-dependent kinase inhibitor, and an increase of caspase-3 activity. Additionally, electron microscopic analysis confirmed that activation of the p53-mediated pathway in HSC results in chromatin and cytoplasmic condensation, typical features of ongoing apoptosis. Our results indicate that transduction of p53 or pRb offers a feasible approach to induce apoptosis in activated HSC. Thus, targeted transfer of these proteins into HSC may be potentially useful for the treatment of hepatic fibrosis.
doi_str_mv 10.1016/s0168-8278(02)00361-6
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Liver. Pancreas. Abdomen</topic><topic>Gene Transfer Techniques</topic><topic>Genetic Therapy - methods</topic><topic>Hepatocytes - cytology</topic><topic>Hepatocytes - physiology</topic><topic>Liver Cirrhosis - pathology</topic><topic>Liver Cirrhosis - therapy</topic><topic>Medical sciences</topic><topic>Ophthalmology</topic><topic>Rats</topic><topic>Retinoblastoma Protein - genetics</topic><topic>Retinopathies</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ABRISS, Bärbel</creatorcontrib><creatorcontrib>HOLLWEG, Günter</creatorcontrib><creatorcontrib>GRESSNER, Axel M</creatorcontrib><creatorcontrib>WEISKIRCHEN, Ralf</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>ABRISS, Bärbel</au><au>HOLLWEG, Günter</au><au>GRESSNER, Axel M</au><au>WEISKIRCHEN, Ralf</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adenoviral-mediated transfer of p53 or retinoblastoma protein blocks cell proliferation and induces apoptosis in culture-activated hepatic stellate cells</atitle><jtitle>Journal of hepatology</jtitle><addtitle>J Hepatol</addtitle><date>2003-02-01</date><risdate>2003</risdate><volume>38</volume><issue>2</issue><spage>169</spage><epage>178</epage><pages>169-178</pages><issn>0168-8278</issn><eissn>1600-0641</eissn><coden>JOHEEC</coden><abstract>The principal cellular effectors of fibrosis in liver are hepatic stellate cells (HSC). 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subjects Adenoviridae - genetics
Animals
Apoptosis - physiology
Biological and medical sciences
Cell Differentiation - physiology
Cell Division - physiology
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - genetics
Fibroblasts - cytology
Fibroblasts - physiology
Gastroenterology. Liver. Pancreas. Abdomen
Gene Transfer Techniques
Genetic Therapy - methods
Hepatocytes - cytology
Hepatocytes - physiology
Liver Cirrhosis - pathology
Liver Cirrhosis - therapy
Medical sciences
Ophthalmology
Rats
Retinoblastoma Protein - genetics
Retinopathies
Tumor Suppressor Protein p53 - genetics
Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus
title Adenoviral-mediated transfer of p53 or retinoblastoma protein blocks cell proliferation and induces apoptosis in culture-activated hepatic stellate cells
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