Tankyrase

Genomic sequence analysis has identified 17 structurally related proteins containing a PARP catalytic domain [3] however, closer inspection suggests that only PARPs 1-3, PARP-4 (vault PARP), and tankyrases 1 and 2 may truly function as poly(ADP-ribosyl)ating proteins. The remaining... 

TANKYRASE INHIBITION AS A STRATEGY FOR Wnt/p-CATENIN PATHWAY MODULATION... 

Chemistry. Nicotinamide (NAm), a product of PARP-1 enzymatic action on NAD and a weak inhibitor of PARP-1 activity (Curtin, 2006), was used as a model for the first PARP-1 inhibitors, including benzamide and 3-aminobenzamide (3AB) (Shall, 1975) (Fig. 7a). Benzamide and 3AB inhibit PARP-1 activity in the mM range and may also inhibit other PARP family members e.g., PARP-2 and tankyrase Smith et al, 1998 Ame et al, 1999), thus lacking the potency and specificity required for therapeutic purposes. Banasik et al developed 1,5-dihydroisoquinoline (Fig. 7c) and a variety of other inhibitors (Banasik et al, 1992), which were used in turn to develop even more inhibitors with greater specificity. 

Huang SM, Mishina YM, Liu S et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461 614-620... 

PARP is a family of enzymes including PARP-1, PARP-2, PARP-3, tankyrase, and V-PARP (8)PARP-1 is perhaps the most important enzyme involved in DNA repair in stroke. However, if PARP-1 is deactivated, perhaps the other enzymes can take its place. The PARP inhibitors described so far in the literature are PARP-1 inhibitors. It is not known whether these compounds also inhibit the. other forms of PARP. 

S. Smith, I. Giriat, A. Schmitt, et al. Tankyrase, a poly (ADPribose) polymerase at human telomeres. Science 282, 1484 (1998). 

Sbodio JI, Lodish HF, Chi NW. Tankyrase-2 oligomerizes with tankyra e-l and binds to both TRFl (telomererepeat-binding factor 1) and IRAP (insulinresponsive aminopeptidase). Biochem J 2002 361(Pt 3) 451-9. 

Rippmann JF, Damm K, Schnapp A. Functional characterization of the poly(ADP-ribose) polymerase activity of tankyrase 1, a potential regulator of telomere length. J Mol Biol 2002 323(2) 217-24. 

Smith S, de Lange T. Tankyrase promotes telomere elongation in human cells. Curr Biol 2000 10(20) 1299-302. 

Smith S, de Lange T. Cell cycle dependent localization of the telomeric PARP, tankyrase, to nuclear pore complexes and centrosomes. J Cell Sci 1999 112(Pt 21) 16 3649-56. 

Lyons RJ, Deane R, Lynch DK et al. Identification of a novel human tankyrase through its interaction with the adaptor protein Grbl4. J Biol Chem 2001 276(20) 17172-80. 

Five years ago, we isolated a cDNA encoding a 62 IcDa protein sharit considerable homology with the catalytic domain of PARP-1. The assumption that we were dealii with a novel PARP enzyme was supported by the discovery in Arahidopsis thaUana of a gene coding for a PARP related polypeptide of a calculated mass of 72 kDa and by the identification of two PARP homologues one present at telomeres (Tankyrase 1) and a second present in Vault particles (VPARP). Hence, the protein encoded by this new cDNA was named PARP-2. 

Cook BD, Dynek JN, Chang W et al. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol 2002 22(l) 332-342. 

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