Targeted deletion of hepatocyte Ikkbeta confers growth advantages.
Mice lacking hepatocyte IKKbeta (Ikkbeta(Delta hep)) are defective in TNFalpha-activation of hepatocellular transcription factor NF-kappaB, and highly susceptible to hepatotoxicity. Following diethylnitrosamine (DEN) exposure, Ikkbeta(Delta hep) mice develop more hepatocellular carcinoma (HCC) than control mice due partly to enhanced DEN-induced hepatocyte death. Here we show that Ikkbeta(Delta hep) hepatocytes display growth advantages over normal hepatocytes consisting of precocious PCNA and cyclin D1 expression during liver regeneration (shortened hepatocyte G(0)-->G(1) transitions), and enhanced recovery efficiency, cyclin D1 expression and cell proliferation after plating. Ex vivo deletion of Ikkbeta also accelerates hepatocyte growth. Ikkbeta(Delta hep) hepatocyte proliferative responses show heightened sensitivity to TGFalpha and TNFalpha, and heightened expression of fibronectin, collagens I/III, nidogen, beta-actin and integrin beta1 mRNAs. These findings suggest that altered mitogen signaling and expression of extracellular matrix and its associated components underlie growth advantages. Increased HCC development in Ikkbeta(Delta hep) mice may also be caused by growth advantages of surviving Ikkbeta-deleted hepatocytes.
Koch
Katherine S
KS
Hepatocyte Growth Control and Stem Cell Laboratory, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0636, La Jolla, CA 92093-0636, USA.
Maeda
Shin
S
He
Guobin
G
Karin
Michael
M
Leffert
Hyam L
HL
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis; D016193:G1 Phase / Q000235:genetics; D017353:Gene Deletion; D018390:Gene Targeting; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D008115:Liver Regeneration / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C530105:Ccnd1 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse