The role of nuclear factor kappaB in late-gestation liver development in the rat.
During the last 3 days of fetal development in the rodent, a burst of hepatocyte proliferation results in a tripling of liver size. Despite stimulation of mitogenesis via multiple signaling pathways, including some that are considered stress response pathways, little apoptosis accompanies this cell growth. Given the accepted role of nuclear factor kappaB (NF-kappaB) in preventing hepatocellular apoptosis during proliferation in mid-development, we predicted that NF-kappaB would be functional during the period of rapid growth during late gestation in the rat. NF-kappaB binding in electrophoretic mobility shift assays was low in embryonic day (E) 19 liver nuclear extracts relative to adult liver nuclear extracts. An additional band that was present in E19 liver was purified and identified as nucleolin. Tumor necrosis factor alpha (TNF-alpha) administration to E19 embryos in utero produced minimal induction of NF-kappaB p50 homodimers and p50/p65 heterodimers, yet baseline apoptosis was not affected. Although p65 was present in E19 hepatocyte cytoplasm in amounts comparable to adult liver, we observed little translocation of p65 to the liver nuclei following TNF-alpha administration. Additionally, expression of several NF-kappaB-responsive genes remained minimally induced in E19 liver following TNF-alpha treatment. In conclusion, although the NF-kappaB components are present in late-gestation fetal liver, NF-kappaB as a transcription factor is relatively inactive and unresponsive to TNF-alpha. Given this finding and the high level of proliferation in late-gestation fetal liver, we predict that alternative antiapoptotic mechanisms are active during this period of rapid hepatic growth.
Embree-Ku
Michelle
M
Department of Pediatrics, Rhode Island Hospital, MPS-215, 593 Eddy Street, Providence, RI 02903, USA. michelle_embree@brown.edu
Gruppuso
Philip A
PA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000196:embryology*; D008297:Male; D016328:NF-kappa B / Q000032:analysis / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases