• Telomere shortening impairs organ regeneration by inhibiting cell cycle re-entry of a subpopulation of cells

      Satyanarayana, A.; Wiemann, S.U.; Buer, J.; Lauber, J.; Dittmar, K.E.J.; Wüstefeld, T.; Blasco, M.A.; Manns, M.P.; Rudolph, K.L. (Oxford University Press, 2003-08-01)
    • Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer.

      Timmerbeul, Inke; Garrett-Engele, Carrie M; Kossatz, Uta; Chen, Xueyan; Firpo, Eduardo; Grünwald, Viktor; Kamino, Kenji; Wilkens, Ludwig; Lehmann, Ulrich; Buer, Jan; et al. (2006-09-19)
      Decreased expression of the CDK inhibitor p27kip1 in human tumors directly correlates with increased resistance to chemotherapies, increased rates of metastasis, and an overall increased rate of patient mortality. It is thought that decreased p27 expression in tumors is caused by increased proteasomal turnover, in particular activation of the pathway governed by the SCFskp2 E3 ubiquitin protein ligase. We have directly tested the importance of the SCFskp-mediated degradation of p27 in tumorigenesis by analyzing the tumor susceptibility of mice that express a form of p27 that cannot be ubiquitinated and degraded by this pathway (p27T187A). In mouse models of both lung and colon cancer down-regulation of p27 promotes tumorigenesis. However, we found that preventing p27 degradation by the SCFskp2 pathway had no impact on tumor incidence or overall survival in either tumor model. Our study unveiled a previously unrecognized role for the control of p27 mRNA abundance in the development of non-small cell lung cancers. In the colon cancer model, the frequency of intestinal adenomas was similarly unaffected by the p27T187A mutation, but, unexpectedly, we found that it inhibited progression of intestinal adenomas to carcinomas. These studies may guide the choice of clinical settings in which pharmacologic inhibitors of the Skp2 pathway might be of therapeutic value.
    • Type I interferon drives tumor necrosis factor-induced lethal shock.

      Huys, Liesbeth; Van Hauwermeiren, Filip; Dejager, Lien; Dejonckheere, Eline; Lienenklaus, Stefan; Weiss, Siegfried; Leclercq, Georges; Libert, Claude; Department for Molecular Biomedical Research, VIB, Ghent B9052, Belgium. (2009-08-31)
      Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN-alpha receptor 1 (IFNAR-1) or in IFN-beta are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1(-/-) mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1(-/-) mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element-dependent genes, many of which encode chemokines. In livers of IFNAR-1(-/-) mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.