The Fn14 Immediate-Early Response Gene Is Induced During Liver Regeneration and Highly Expressed in Both Human and Murine Hepatocellular Carcinomas

Abstract

Polypeptide growth factors stimulate mammalian cell proliferation by binding to specific cell surface receptors. This interaction triggers numerous biochemical responses including the activation of protein phosphorylation cascades and the enhanced expression of specific genes. We have identified several fibroblast growth factor (FGF)-inducible genes in murine NIH 3T3 cells and recently reported that one of them, the FGF-inducible 14 (Fn14) immediate-early response gene, is predicted to encode a novel, cell surfacelocalized type Ia transmembrane protein. Here, we report that the human Fn14 homolog is located on chromosome 16p13.3 and encodes a 129-amino acid protein with ϳ82% sequence identity to the murine protein. The human Fn14 gene, like the murine Fn14 gene, is expressed at elevated levels after FGF, calf serum or phorbol ester treatment of fibroblasts in vitro and is expressed at relatively high levels in heart and kidney in vivo. We also report that the human Fn14 gene is expressed at relatively low levels in normal liver tissue but at high levels in liver cancer cell lines and in hepatocellular carcinoma specimens. Furthermore, the murine Fn14 gene is rapidly induced during liver regeneration in vivo and is expressed at high levels in the hepatocellular carcinoma nodules that develop in the c-myc/transforming growth factor-␣-driven and the hepatitis B virus X protein-driven transgenic mouse models of hepatocarcinogenesis. These results indicate that Polypeptide mitogens such as fibroblast growth factor (FGF)-1 and platelet-derived growth factor-BB stimulate cell cycle progression by binding to specific receptor tyrosine kinases and thereby activating intracellular signal transduction pathways.1 The activation of cytoplasmic signaling molecules promotes changes in gene expression that are critical for the cellular growth response. Numerous growth factor-and/or serum-inducible genes have been identified and classified into one of three groups: immediate-early, delayed-early, or late response genes.2 Immediate-early response genes are rapidly and transiently expressed following mitogenic stimulation of quiescent cells and their transcriptional activation does not require de novo protein synthesis. Delayed-early response genes are first expressed a few hours later, in the early to middle portions of the G1 phase, and transcript levels often remain elevated for the remainder of the cell cycle. Late response genes are generally expressed only during the S phase of the cell cycle. Both delayed-early and late response genes require de novo protein synthesis for their transcriptional activation. Growth factor-inducible genes encode many types of proteins, including transcription factors, cell cycle regulators, extracellular matrix proteins and metabolic enzymes. [2][3][4]

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

“…We have found that Fn14 is expressed on erythroid precursor cells, which are characterized by a high proliferative potential. This finding is consistent with previous reports on Fn14 expression in actively dividing tissues, such as the regenerating liver and injured vessel wall (27,45), thus suggesting a general role for Fn14 in balancing cell expansion. TWEAK mRNA is expressed in erythroid precursor cells until the latest maturation stages, whereas TWEAK protein is present at low levels on the plasma membrane.…”

Fibroblast Growth Factor-Inducible 14 Mediates Multiple Pathways of TWEAK-Induced Cell Death

“…The TWEAK receptor turned out to be a fibroblast growth factor-inducible 14-kDa protein, Fn14, which was originally identified by a differential display approach to search for growth factor-inducible molecules in murine NIH3T3 fibroblasts (14,15). Fn14 is a distantly related TNFR family member, which contains only one cysteine-rich domain in the extracellular region and a TNFR-associated factor (TRAF) binding domain, but not the DD, in the cytoplasmic region (13).…”

Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

“…13 Although TWEAK is almost ubiquitously expressed in adult tissues, including the liver, its cognate receptor is barely detectable in hepatic tissue except during injury and repair. Feng et al 14 reported rapid induction of Fn14 expression during the early phases of regeneration following partial hepatectomy. The authors also investigated liver cancer-derived cell lines, and interestingly, Fn14 overexpression was mainly found in the poorly differentiated lines; this hinted at possible involvement in progenitor cells.…”