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UPREGULATION OF PI3K‐AKT PATHWAY FOLLOWING TREATMENT WITH EGFR SPECIFIC shRNA IN REGENERATING RAT LIVERS
Author(s) -
Paranjpe Shirish,
Bowen William C.,
George Tseng C.,
Luo JianHua,
Orr Ann V.,
Michalopoulos George K.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.349.3
Subject(s) - downregulation and upregulation , pi3k/akt/mtor pathway , liver regeneration , protein kinase b , erbb , small hairpin rna , cancer research , gene silencing , erbb3 , regeneration (biology) , epidermal growth factor receptor , biology , microbiology and biotechnology , signal transduction , medicine , receptor , apoptosis , gene , biochemistry , gene knockdown
Liver regeneration after two‐third partial hepatectomy (PHx) is a complex process requiring interaction and cooperation of many growth factors and cytokines and crosstalk between multiple pathways. To investigate the role of EGFR in liver regeneration, we used two EGFR specific shRNA to inhibit EGFR expression in regenerating normal rat liver. Suppression of EGFR mRNA and protein was evident in treated rats. There was also a demonstrable decrease but not complete elimination of BrdU incorporation and mitoses at 24 hours after PHx, proapoptotic genes were upregulated, and genes associated with cellular proliferation were down regulated. However a compensatory upregulation in ErbB‐3, ErbB‐2, MET and Src resulted in an increase in formation of ErbB‐3‐ErbB‐2 heterodimers which in turn activated the PI3K‐Akt survival pathway and restoration of liver mass by hepatic hypertrophy. However, we did not observe any mortality associated with silencing of EGFR and no delay in regeneration was observed in EGFR silenced rats. The data indicate that although the MET and EGFR pathways are similar, the contributions made by MET and EGFR are unique and are not compensated by each other or other cytokines.