Characterization of PDGF-B and TRIM47, two target genes downstream of TNF and NF-kappaB.

摘要

TNF is a pro-inflammatory cytokine capable of inducing both death and survival signals. The survival pathway is primarily mediated by a genetic program activated by the transcription factor NF-kappaB. Deregulation of TNF and NF-kappaB signals have been implicated in oncogenesis, and may contribute to the relationship between chronic inflammation and cancer. Platelet derived growth factor B (PDGF-B) and TRIM47, also known as "gene overexpressed in astrocytoma," were identified by microarray screening as tumour necrosis factor (TNF) inducible genes that are dependent on NF-kappaB.; PDGF-B, a known growth factor and oncogene, was found to protect NF-kappaB-deficient cells from TNF induced cell death by autocrine/paracrine signaling through the PDGF receptor. Wild type cells were sensitized to TNF induced cell death with PDGFR inhibition, and this correlated with sustained MAPK signaling and elevated reactive oxygen species levels. PDGF-B transformed cells were significantly more susceptible to TNF killing than wild type cells with PDGFR inhibition, suggesting that these malignant cells are highly dependent on PDGF-B signals to evade death receptor-induced apoptosis.; The role of TRIM47 in cell survival signaling is less clear, but initial characterization suggests that TRIM47 may feedback to regulate the NF-kappaB signal and/or crosstalk with the p53 signaling pathway. TRIM47 also appears to be a potential E3 ubiquitin ligase and may modulate NF-kappaB and p53 signals through ubiquitination. TRIM47 also appears to affect NEMO/IKKgamma levels, and physically interact with p53.; Both PDGF-B and TRIM47 suggest that NF-kappaB target genes downstream of TNF may promote cell survival in ways that do not depend on directly opposing TNF cell death machinery. Crosstalk with other pathways---by induction of a cytokine cascade or by influencing other survival and apoptotic signals---likely integrate various signals downstream of TNFR1 to help determine cell fate in response to TNF.