Telomere length and function are crucial factors that determine the capacity for cell proliferation and survival, mediate cellular senescence, and play a role in malignant transformation in eukaryotic systems. The telomere length of a specific mammalian species is maintained within a given range by the action of telomerase and telomereassociated proteins. TRF1 is a telomere-associated protein that inhibits telomere elongation by its binding to telomere repeats, preventing access to telomerase. Human TRF1 interacts with tankyrase 1 and tankyrase 2 proteins, two related members of the tankyrase family shown to have poly(ADP-ribose) polymerase activity. Human tankyrase 1 is reported to ADP-ribosylate TRF1 and to down-regulate the telomeric repeat binding activity of TRF1, resulting in telomerase-dependent telomere elongation. Human tankyrase 2 is proposed to have activity similar to that of tankyrase 1, although tankyrase 2 function has been less extensively characterized. In the present study, we have assessed the in vivo function of mouse tankyrase 2 by germ line gene inactivation and show that inactivation of tankyrase 2 does not result in detectable alteration in telomere length when monitored through multiple generations of breeding. This finding suggests that either mouse tankyrases 1 and 2 have redundant functions in telomere length maintenance or that mouse tankyrase 2 differs from human tankyrase 2 in its role in telomere length maintenance. Tankyrase 2 deficiency did result in a significant decrease in body weight sustained through at least the first year of life, most marked in male mice, suggesting that tankyrase 2 functions in potentially telomeraseindependent pathways to affect overall development and/or metabolism.Telomeres are structures at the ends of linear chromosomes in all eukaryotic cells and consist of tandem DNA repeats and associated proteins (4,8,16). Telomere length is critical for aspects of chromosome stability that affect cell proliferation and survival (4,8). The determination and maintenance of species-specific telomere length settings are controlled by a complex system of regulation that is not completely understood. As a consequence of primer dependence and incomplete replication of chromosomal termini during cell division, eukaryotic telomeres shorten as cells replicate (4, 8). Telomerase, an enzyme consisting of the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT) (4, 8), is capable of compensating for this loss by adding telomeric repeats to chromosome ends. Numerous reports have described additional telomere-associated proteins, including telomeric repeat binding factors 1 and 2 (TRF1 and TRF2) (7), TRF1-interacting protein 2 (TIN2) (20), tankyrases 1 (34) and 2 (18), protein interacting with NIMA-interacting factor 1 (PINX1) (38), Rap1 (25), Rad50 (24), Mre11 (29), Nbs1 (26), ATM (21), WRN (28), ERCC1/XPF (39), and POT1 (2), which individually and through interactions with one another play important roles in telomere length maintenance.Both TRF1 and TRF...

Background: Fn14 is a highly inducible TNF superfamily cytokine receptor. Results: Fn14 undergoes rapid, ligand-independent internalization and degradation mediated by the extracellular domain of the receptor. Conclusion: Fn14 expression is regulated through transcription as described previously and through a novel post-translational mechanism. Significance: Receptor trafficking may play an important role in regulating receptor availability, cytokine responses, and ligand-independent signaling.

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