Molecular Mechanisms Controlling Susceptibitliy to Tumor Necrosis Factor Induced Cell Death

Summary

The receptors of the multifunctional cytokine Tumor Necrosis Factor-α (TNF) belong to a family of structurally related proteins called the TNFR/NGFR-family. Two receptors of this family, TNFR and Fas can trigger cell death in responsive cells. In contrast to Fas, activated TNFR exerts a variety of biologic functions other than death induction. Virus-infected cells, tumor cells and transformed cells are often sensitive to the death-inducing activity of TNF, yet the molecular mechanisms underlying TNF-sensitivity are unclear. We have addressed the question whether normally growing cells may acquire a TNF-sensitive phenotype upon activation of growth-deregulating oncogenes. We have shown that the oncogenic activation of the nuclear phosphoprotein c-Myc renders TNF-resistant fibroblasts sensitive to TNF-mediated death. Moreover, an increased constitutive expression of c-Myc increases the cytotoxic action of TNF. These results suggest that the deregulation of c-Myc, which is common in human tumors and tumor cell lines is one reason why such cells are TNF sensitive. Deregulation of growth by viral or endogenous oncoproteins renders cells more prone to apoptosis in comparison to their normally growing counterparts. The regions of c-Myc required for cell transformation and induction of apoptosis upon growth-factor deprivation are also necessary for the induction of TNF-sensitivity. In addition, the Bcl2 and MnSOD proteins can inhibit the c-Myc dependent apoptosis of growth factor-deprived cells and of TNF-stimulated cells. Deregulation of cell growth may preset the apoptotic machinery and thus render cells susceptible for the death-inducing effects of TNF.