The role of nuclear factor κB in late‐gestation liver development in the rat†

Abstract

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 B (NF-B) in preventing hepatocellular apoptosis during proliferation in mid-development, we predicted that NF-B would be functional during the period of rapid growth during late gestation in the rat. NF-B 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 ␣ (TNF-␣) administration to E19 embryos in utero produced minimal induction of NF-B 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-␣ administration. Additionally, expression of several NF-B-responsive genes remained minimally induced in E19 liver following TNF-␣ treatment. In conclusion, although the NF-B components are present in late-gestation fetal liver, NF-B as a transcription factor is relatively inactive and unresponsive to TNF-␣. Given this finding and the high level of proliferation in lategestation fetal liver, we predict that alternative antiapoptotic mechanisms are active during this period of rapid hepatic growth. (HEPATOLOGY 2005;42:326-334.)

Hepatic translation control in the late-gestation fetal rat

“…The ability of fetal rat hepatocytes to repopulate the adult liver (13) and to proliferate independent of their differentiation status (21) indicates their potential for repair of liver injury. Their mitogen-independent signaling phenotype (7,8) and resistance to apoptosis (15) suggest a relationship to liver carcinogenesis. A potential relationship to mechanisms involved in the development of hepatocellular carcinoma is perhaps best exemplified by the resistance of fetal hepatocytes in vivo to the growth inhibitory effects of rapamycin (6,39).…”

“…Our laboratory has focused on late-gestation liver development in the rat as a model of hepatocyte growth regulation, one that contrasts with the synchronized hepatocyte proliferation that occurs after partial hepatectomy in the adult rat. We have observed a number of differences between the two models, including the activation state of mitogenic signaling pathways (7,8), the expression of cell cycle-regulating genes (4,9), the mechanisms controlling apoptosis (15), and, most relevant to the present studies, the sensitivity of hepatocyte proliferation in vivo to the growth inhibitory effects of rapamycin (6).…”

Nucleolin regulates c-Jun/Sp1-dependent transcriptional activation of cPLA2 in phorbol ester-treated non-small cell lung cancer A549 cells

“…Nucleolin is a matrix attachment region (MAR)-binding protein to provide a link between DNA and nuclear matrix scaffolding (50). In addition, nucleolin was also found to bind to the NFκB DNA-binding motif and the KLF2 promoter (51,52). Thus, nucleolin may interact with DNA and other transcriptional factors, such as c-Jun, to regulate transcription.…”

Does nucleolin bind the NF kappa B DNA binding motif?

“…1 Nucleolin binding to the canonical NFB target sequence was not a central theme of the paper, but rather an issue we felt compelled to address because its presence explained the only dark band on the EMSAs for NFB using fetal nuclear extract. A considerable amount of time and effort was spent identifying nucleolin.…”