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• W2005477432 abstract "Mcl-1L (myeloid cell leukemia-1 long) is an antiapoptotic Bcl-2 family protein discovered as an early induction gene during leukemia cell differentiation. Previously, we identified Mcl-1S (short) as a short splicing variant of theMcl-1 gene with proapoptotic activity. To identify Mcl-1-interacting proteins, we performed yeast two-hybrid screening and found cDNAs encoding tankyrase 1. This protein possesses poly(ADP-ribose) polymerase activity and presumably facilitates the turnover of substrates following ADP-ribosylation. In yeast and mammalian cells, tankyrase 1 interacts with both Mcl-1L and Mcl-1S, but does not bind to other Bcl-2 family proteins tested. Analysis of truncated tankyrase 1 mutants indicated that the first 10 ankyrin repeats are involved in interaction with Mcl-1. In the N terminus of Mcl-1, a stretch of 25 amino acids is sufficient for binding to tankyrase 1. Overexpression of tankyrase 1 antagonizes both Mcl-1L-mediated cell survival and Mcl-1S-induced cell death. Furthermore, coexpression of tankyrase 1 with Mcl-1L or Mcl-1S decreased the levels of Mcl-1 proteins. Although tankyrase 1 down-regulates Mcl-1 protein expression, no ADP-ribosylation of Mcl-1 was detected. In contrast, overexpression of Mcl-1 proteins suppressed the ADP-ribosylation of the telomeric repeat binding factor 1, another tankyrase 1-interacting protein. Thus, interaction of Mcl-1L and Mcl-1S with tankyrase 1 could serve as a unique mechanism to decrease the expression of these Bcl-2 family proteins, thereby leading to the modulation of the apoptosis pathway. Mcl-1L (myeloid cell leukemia-1 long) is an antiapoptotic Bcl-2 family protein discovered as an early induction gene during leukemia cell differentiation. Previously, we identified Mcl-1S (short) as a short splicing variant of theMcl-1 gene with proapoptotic activity. To identify Mcl-1-interacting proteins, we performed yeast two-hybrid screening and found cDNAs encoding tankyrase 1. This protein possesses poly(ADP-ribose) polymerase activity and presumably facilitates the turnover of substrates following ADP-ribosylation. In yeast and mammalian cells, tankyrase 1 interacts with both Mcl-1L and Mcl-1S, but does not bind to other Bcl-2 family proteins tested. Analysis of truncated tankyrase 1 mutants indicated that the first 10 ankyrin repeats are involved in interaction with Mcl-1. In the N terminus of Mcl-1, a stretch of 25 amino acids is sufficient for binding to tankyrase 1. Overexpression of tankyrase 1 antagonizes both Mcl-1L-mediated cell survival and Mcl-1S-induced cell death. Furthermore, coexpression of tankyrase 1 with Mcl-1L or Mcl-1S decreased the levels of Mcl-1 proteins. Although tankyrase 1 down-regulates Mcl-1 protein expression, no ADP-ribosylation of Mcl-1 was detected. In contrast, overexpression of Mcl-1 proteins suppressed the ADP-ribosylation of the telomeric repeat binding factor 1, another tankyrase 1-interacting protein. Thus, interaction of Mcl-1L and Mcl-1S with tankyrase 1 could serve as a unique mechanism to decrease the expression of these Bcl-2 family proteins, thereby leading to the modulation of the apoptosis pathway. Phylogenetically conserved Bcl-2 family proteins play a pivotal role in the regulation of apoptosis from virus to human (1Adams J.M. Cory S. Science. 1998; 281: 1322-1326Crossref PubMed Scopus (4780) Google Scholar). Members of the Bcl-2 family consist of antiapoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w, and proapoptotic proteins such as BAD, Bax, BOD, and Bok. It has been proposed that anti- and proapoptotic Bcl-2 proteins regulate cell death by binding to each other and forming heterodimers (2Yang E. Zha J. Jockel J. Boise L.H. Thompson C.B. Korsmeyer S.J. Cell. 1995; 80: 285-291Abstract Full Text PDF PubMed Scopus (1883) Google Scholar). A delicate balance between anti- and proapoptotic Bcl-2 family members exists in each cell and the relative concentration of these two groups of proteins determines whether the cell survives or undergoes apoptosis.Myeloid cell leukemia-1(Mcl-1) 1The abbreviations used are: Mcl-1, myeloid cell leukemia-1; BH domain, Bcl-2 homology domain; Mcl-1L, Mcl-1 long; Mcl-1S, Mcl-1 short; TRF1, telomeric repeat binding factor 1; CHO, Chinese hamster ovary; HA, hemagglutinin; PARP, poly(adenosine diphosphate ribose) polymerase; IRAP, insulin-responsive aminopeptidase 1The abbreviations used are: Mcl-1, myeloid cell leukemia-1; BH domain, Bcl-2 homology domain; Mcl-1L, Mcl-1 long; Mcl-1S, Mcl-1 short; TRF1, telomeric repeat binding factor 1; CHO, Chinese hamster ovary; HA, hemagglutinin; PARP, poly(adenosine diphosphate ribose) polymerase; IRAP, insulin-responsive aminopeptidase is a Bcl-2 family protein and was originally cloned as a differentiation-induced early gene that was activated in a human myeloblastic leukemia cell line (3Kozopas K.M. Yang T. Buchan H.L. Zhou P. Craig R.W. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3516-3520Crossref PubMed Scopus (873) Google Scholar). Mcl-1 is expressed in a wide variety of tissues and cells including neoplastic ones (3Kozopas K.M. Yang T. Buchan H.L. Zhou P. Craig R.W. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3516-3520Crossref PubMed Scopus (873) Google Scholar, 4Krajewski S. Bodrug S. Krajewska M. Shabaik A. Gascoyne R. Berean K. Reed J.C. Am. J. Pathol. 1995; 146: 1309-1319PubMed Google Scholar, 5Yang T. Kozopas K.M. Craig R.W. J. Cell Biol. 1995; 128: 1173-1184Crossref PubMed Scopus (270) Google Scholar). We and others recently identified a short splicing variant of Mcl-1 short (Mcl-1S) and designated the known Mcl-1 as Mcl-1 long (Mcl-1L) (6Bae J. Leo C.P. Hsu S.Y. Hsueh A.J. J. Biol. Chem. 2000; 275: 25255-25261Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 7Bingle C.D. Craig R.W. Swales B.M. Singleton V. Zhou P. Whyte M.K. J. Biol. Chem. 2000; 275: 22136-22146Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). Mcl-1L protein exhibits antiapoptotic activity and possesses the BH (Bcl-2 homology) 1, BH2, BH3, and transmembrane domains found in the related Bcl-2 proteins (3Kozopas K.M. Yang T. Buchan H.L. Zhou P. Craig R.W. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3516-3520Crossref PubMed Scopus (873) Google Scholar, 5Yang T. Kozopas K.M. Craig R.W. J. Cell Biol. 1995; 128: 1173-1184Crossref PubMed Scopus (270) Google Scholar, 8Zhou P. Qian L. Bieszczad C.K. Noelle R. Binder M. Levy N.B. Craig R.W. Blood. 1998; 92: 3226-3239Crossref PubMed Google Scholar). In contrast, Mcl-1S is a BH3 domain-only proapoptotic protein that heterodimerizes with Mcl-1L (6Bae J. Leo C.P. Hsu S.Y. Hsueh A.J. J. Biol. Chem. 2000; 275: 25255-25261Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). Although both Mcl-1L and Mcl-1S proteins contain BH domains found in other Bcl-2 family proteins, they are distinguished by their unusually long N-terminal sequences containing PEST (proline, glutamic acid, serine, and threonine) motifs, four pairs of arginine residues, and alanine- and glycine-rich regions. In addition, the tissue expression pattern of the Mcl-1 protein is different from that of Bcl-2 suggesting a unique role for Mcl-1 in apoptosis regulation (4Krajewski S. Bodrug S. Krajewska M. Shabaik A. Gascoyne R. Berean K. Reed J.C. Am. J. Pathol. 1995; 146: 1309-1319PubMed Google Scholar, 5Yang T. Kozopas K.M. Craig R.W. J. Cell Biol. 1995; 128: 1173-1184Crossref PubMed Scopus (270) Google Scholar).Tankyrase 1 (TRF1-interacting,ankyrin-elated ADP-ribose polymerase 1) was originally isolated based on its binding to TRF1 (telomeric repeat bindingfactor-1) and contains the HPS (homopolymeric runs of histidine, proline, and serine) sequence, 24 ankyrin repeats, SAM (sterile α-motif), and the catalytic domain of poly(adenosine diphosphate-ribose) polymerase (PARP) (9Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (895) Google Scholar). Previous studies have shown that tankyrase 1 promotes telomere elongation in human cells by inhibiting TRF1 through its poly(ADP-ribosyl)ation by tankyrase 1 (9Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (895) Google Scholar, 10Smith S. de Lange T. Curr. Biol. 2000; 10: 1299-1302Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar). In addition, tankyrase 1 poly(ADP-ribosyl)atesinsulin-responsive aminopeptidase (IRAP), a resident protein of GLUT4 vesicles, and insulin stimulates the PARP activity of tankyrase 1 through its phosphorylation by mitogen-activated protein kinase (11Chi N.W. Lodish H.F. J. Biol. Chem. 2000; 275: 38437-38444Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). Recently, tankyrase 1 also has been shown to poly(ADP-ribosyl)ate TAB182 (tankyrase-binding protein of182-kDa protein) (12Seimiya H. Smith S. J. Biol. Chem. 2002; 277: 14116-14126Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). ADP-ribosylation is a post-translational modification mechanism that usually results in a loss of protein activity presumably by enhancing protein turnover (13Althaus F.R. Richter C. Mol. Biol. Biochem. Biophys. 1987; 37: 1-237PubMed Google Scholar, 14Burkle A. Biogerontology. 2000; 1: 41-46Crossref PubMed Scopus (35) Google Scholar, 15de Murcia G. Schreiber V. Molinete M. Saulier B. Poch O. Masson M. Niedergang C. Menissier de Murcia J. Mol. Cell. Biochem. 1994; 138: 15-24Crossref PubMed Scopus (186) Google Scholar, 16D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (0) Google Scholar). However, little information is available regarding the physiological function(s) of tankyrase 1 other than as a PARP enzyme.In the present study, we found tankyrase 1 as a specific-binding protein of Mcl-1. Overexpression of tankyrase 1 led to the inhibition of both the survival action of Mcl-1L and the apoptotic activity of Mcl-1S in mammalian cells. Unlike other known tankyrase 1-interacting proteins, tankyrase 1 did not poly(ADP-ribosyl)ate either of the Mcl-1 proteins despite its ability to decrease Mcl-1 protein levels following coexpression. Therefore, tankyrase 1 could regulate Mcl-1-modulated apoptosis by down-regulating the expression of Mcl-1 proteins without the involvement of its ADP-ribosylation activity.DISCUSSIONMcl-1, a unique Bcl-2 family protein, is transiently induced by various growth factors and shows a rapid turnover rate (20Akgul C. Moulding D.A. White M.R. Edwards S.W. FEBS Lett. 2000; 478: 72-76Crossref PubMed Scopus (83) Google Scholar, 21Schubert K.M. Duronio V. Biochem. J. 2001; 356: 473-480Crossref PubMed Scopus (67) Google Scholar). Earlier studies demonstrated that Mcl-1 expression is up-regulated by epidermal growth factor, elk-1, granulocyte-macrophage colony-stimulating factor, gonadotropins, stem cell factor, interferon-α, and different interleukins in diverse cell lineages (22Puthier D. Thabard W. Rapp M. Etrillard M. Harousseau J. Bataille R. Amiot M. Br. J. Haematol. 2001; 112: 358-363Crossref PubMed Scopus (46) Google Scholar, 23Townsend K.J. Trusty J.L. Traupman M.A. Eastman A. Craig R.W. Oncogene. 1998; 17: 1223-1234Crossref PubMed Scopus (97) Google Scholar, 24Townsend K.J. Zhou P. Qian L. Bieszczad C.K. Lowrey C.H. Yen A. Craig R.W. J. Biol. Chem. 1999; 274: 1801-1813Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 25Wang J.M. Chao J.R. Chen W. Kuo M.L. Yen J.J. Yang-Yen H.F. Mol. Cell. Biol. 1999; 19: 6195-6206Crossref PubMed Google Scholar, 26Wei L.H. Kuo M.L. Chen C.A. Chou C.H. Cheng W.F. Chang M.C. Su J.L. Hsieh C.Y. Oncogene. 2001; 20: 5799-5809Crossref PubMed Scopus (148) Google Scholar). Despite numerous studies on the induction of Mcl-1, no information is available regarding the suppression of the rapidly induced Mcl-1 proteins. Based on yeast two-hybrid screening, we identified an Mcl-1-interacting protein, tankyrase 1, that could provide a novel mechanism to decrease the levels and to suppress the actions of both Mcl-1L and its splicing variant Mcl-1S.We demonstrated that overexpression of tankyrase 1 suppressed cell survival induced by Mcl-1L. In addition, tankyrase 1 also effectively blocked apoptosis induced by Mcl-1S. In contrast, overexpression of tankyrase 1 itself exhibited no significant effect on CHO cell viability, consistent with a recent observation (34Kaminker P.G. Kim S.H. Taylor R.D. Zebarjadian Y. Funk W.D. Morin G.B. Yaswen P. Campisi J. J. Biol. Chem. 2001; 276: 35891-35899Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). Furthermore, immunoblot studies showed that coexpression of tankyrase 1 resulted in lower levels of both Mcl-1L and Mcl-1S proteins. Thus, tankyrase 1-mediated changes in cell viability may be related to its ability to down-regulate Mcl-1 proteins. The finding of endogenous interactions between Mcl-1L and tankyrase 1 in a human leukemia cell line further supports the physiological importance of the present findings.More than 20 known mammalian Bcl-2 family proteins share common regulatory mechanisms to modulate apoptosis. They dimerize with other Bcl-2 family members (1Adams J.M. Cory S. Science. 1998; 281: 1322-1326Crossref PubMed Scopus (4780) Google Scholar) or interact with specific interacting proteins. For instance, BAD binding to 14-3-3 proteins suppresses the apoptotic activity of BAD (18Hsu S.Y. Kaipia A. Zhu L. Hsueh A.J. Mol. Endocrinol. 1997; 11: 1858-1867Crossref PubMed Scopus (164) Google Scholar, 27Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar), whereas Bim/BOD binding to the LC8 dynein light chain leads to its sequestration to the microtubule-associated dynein motor complex (28Puthalakath H. Huang D.C. O'Reilly L.A. King S.M. Strasser A. Mol. Cell. 1999; 3: 287-296Abstract Full Text Full Text PDF PubMed Scopus (904) Google Scholar). Likewise, Bmf interacts with the dynein light chain 2 before being sequestered to the myosin V actin motor complex (29Puthalakath H. Villunger A. O'Reilly L.A. Beaumont J.G. Coultas L. Cheney R.E. Huang D.C. Strasser A. Science. 2001; 293: 1829-1832Crossref PubMed Scopus (497) Google Scholar), leading to apoptosis suppression. Here, we have demonstrated that both Mcl-1L and Mcl-1S are strongly associated with tankyrase 1 in yeast and mammalian cells. Interactions of tankyrase 1 with Mcl-1 proteins were specific because none of the other members of the Bcl-2 family that were tested bound to tankyrase 1.The antiapoptotic Mcl-1L protein consists of two consensus PEST sequences as well as the BH3, BH1, BH2, and a transmembrane domain. However, the proapoptotic splicing variant, Mcl-1S, possesses only the PEST sequences and the BH3 domain. The common N-terminal end of both Mcl-1 proteins contain the two PEST motifs and four pairs of arginine residues found in rapidly degraded proteins such as c-Myc and p53 (30Rogers S. Wells R. Rechsteiner M. Science. 1986; 234: 364-368Crossref PubMed Scopus (1946) Google Scholar). Although the deletion of these two PEST sequences in Mcl-1 does not affect the half-life of the mutant protein (20Akgul C. Moulding D.A. White M.R. Edwards S.W. FEBS Lett. 2000; 478: 72-76Crossref PubMed Scopus (83) Google Scholar), the extreme N-terminal end of Mcl-1 has a stretch of residues with a weak PEST homology. We demonstrated that the binding of Mcl-1 proteins to tankyrase 1 involves this short stretch of 25 amino acids (76 to 100). Of interest, the same region also contains aRPPPIG sequence that resembles the consensus tankyrase-binding motif (RXXPDG) found in other tankyrase 1-interacting proteins (31Sbodio J.I. Lodish H.F. Chi N.W. Biochem. J. 2002; 361: 451-459Crossref PubMed Scopus (108) Google Scholar).Tankyrase 1 possesses four distinct motifs: the HPS module, 24 ankyrin motifs, SAM, and the catalytic domain of PARP (9Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (895) Google Scholar). Tankyrase 1 is a unique protein with structural features found in both ankyrin and PARP family genes. Ankyrin family proteins are linkers that couple diverse membrane proteins via ankyrin motifs to the underlying cytoskeleton (32Bennett V. Chen L. Curr. Opin. Cell Biol. 2001; 13: 61-67Crossref PubMed Scopus (140) Google Scholar, 33Rubtsov A.M. Lopina O.D. FEBS Lett. 2000; 482: 1-5Crossref PubMed Scopus (107) Google Scholar). All known tankyrase 1-interacting proteins (TRF1, IRAP, and TAB182) bind to tankyrase 1 through ankyrin repeat regions (9Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (895) Google Scholar, 11Chi N.W. Lodish H.F. J. Biol. Chem. 2000; 275: 38437-38444Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 12Seimiya H. Smith S. J. Biol. Chem. 2002; 277: 14116-14126Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Likewise, our data indicated that interactions between Mcl-1 proteins and tankyrase 1 also involved the ankyrin motifs, and the first half of the ankyrin repeats (1 to 12) was sufficient for dimerization. Of particular interest, TRF1 and Mcl-1 are capable of binding to overlapping ankyrin repeats in tankyrase 1, suggesting potential competition between these tankyrase 1-interacting proteins.Tankyrase 1 contains the catalytic domain of PARP and is known to poly(ADP-ribosyl)ate its interacting proteins, TRF1, IRAP, and TAB182 (9Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (895) Google Scholar, 11Chi N.W. Lodish H.F. J. Biol. Chem. 2000; 275: 38437-38444Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 12Seimiya H. Smith S. J. Biol. Chem. 2002; 277: 14116-14126Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). PARP family proteins catalyze the attachment of the poly(ADP-ribose) moiety onto a protein acceptor using the substrate NAD+ (nicotinamide adenine dinucleotide), and ADP-ribosylation of proteins usually leads to protein inactivation (13Althaus F.R. Richter C. Mol. Biol. Biochem. Biophys. 1987; 37: 1-237PubMed Google Scholar, 14Burkle A. Biogerontology. 2000; 1: 41-46Crossref PubMed Scopus (35) Google Scholar, 15de Murcia G. Schreiber V. Molinete M. Saulier B. Poch O. Masson M. Niedergang C. Menissier de Murcia J. Mol. Cell. Biochem. 1994; 138: 15-24Crossref PubMed Scopus (186) Google Scholar, 16D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (0) Google Scholar). However, our study demonstrated that tankyrase 1 does not poly(ADP-ribosyl)ate either of the Mcl-1 proteins. Furthermore, a tankyrase 1 mutant with the PARP domain deleted is still capable of decreasing the Mcl-1 protein levels and blocking the actions of the Mcl-1 proteins. These data suggest that the ability of tankyrase 1 to suppress both anti- and pro-apoptotic actions of the Mcl-1 proteins is not mediated by ADP-ribosylation of these proteins. The findings also suggest that tankyrase 1-interacting proteins are not always the substrates for tankyrase 1. Consistent with the unique structural features and subcellular localization of tankyrase 1, the current study suggests that tankyrase 1 is different from other PARP enzymes (9Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (895) Google Scholar, 11Chi N.W. Lodish H.F. J. Biol. Chem. 2000; 275: 38437-38444Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar,35Smith S. de Lange T. J. Cell Sci. 1999; 112: 3649-3656Crossref PubMed Google Scholar, 36Smith S. Trends Biochem. Sci. 2001; 26: 174-179Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar) and could have nonenzymatic functions. Of interest, tankyrase 2, a gene with 83% sequence identity to tankyrase 1, has recently been isolated (37Kuimov A.N. Kuprash D.V. Petrov V.N. Vdovichenko K.K. Scanlan M.J. Jongeneel C.V. Lagarkova M.A. Nedospasov S.A. Genes Immun. 2001; 2: 52-55Crossref PubMed Scopus (37) Google Scholar, 38Lyons R.J. Deane R. Lynch D.K. Ye Z.S. Sanderson G.M. Eyre H.J. Sutherland G.R. Daly R.J. J. Biol. Chem. 2001; 276: 17172-17180Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar) and found to induce cell death in different cell lines (34Kaminker P.G. Kim S.H. Taylor R.D. Zebarjadian Y. Funk W.D. Morin G.B. Yaswen P. Campisi J. J. Biol. Chem. 2001; 276: 35891-35899Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar).In addition to the tankyrase 1 regulation of Mcl-1 functions, Mcl-1 proteins could reciprocally regulate the function of tankyrase 1. When Mcl-1L or Mcl-1S are coincubated with tankyrase 1, auto-ADP-ribosylation of tankyrase 1 decreases in a Mcl-1 concentration-dependent manner. Although the physiological significance of the apparent decrease in poly(ADP-ribosyl)ation of tankyrase 1 is still unclear and one cannot completely rule out the nonspecific effects of unknown contaminants in the purified Mcl-1 preparation, Mcl-1 proteins caused a more profound suppression of the poly(ADP-ribosyl)ation of TRF1 in the same in vitro test. Because both Mcl-1 proteins and TRF1 interact with the ankyrin repeats in tankyrase 1, Mcl-1 proteins could compete with TRF1 for binding to tankyrase 1, leading to lower ADP-ribosylation of TRF1. Because tankyrase 1-mediated telomere extension is dependent on ADP-ribosylation of TRF1 (10Smith S. de Lange T. Curr. Biol. 2000; 10: 1299-1302Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar), inhibition of the ADP-ribosylation of TRF1 by Mcl-1 could prevent telomere elongation and facilitate cell senescence. This is consistent with the ability of tankyrase 1 to suppress the survival action of Mcl-1L, thus leading to the prevention of cell immortalization.Recent studies indicated that Mcl-1L is localized to the nucleus (39Fujise K. Zhang D. Liu J. Yeh E.T. J. Biol. Chem. 2000; 275: 39458-39465Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar,40Zhang D. Li F. Weidner D. Mnjoyan Z.H. Fujise K. J. Biol. Chem. 2002; 277: 37430-37438Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). and is involved in cell cycle regulation by interacting with the proliferating cell nuclear antigen (39Fujise K. Zhang D. Liu J. Yeh E.T. J. Biol. Chem. 2000; 275: 39458-39465Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Mcl-1 also serves as a nuclear chaperone for another antiapoptotic protein, fortilin (40Zhang D. Li F. Weidner D. Mnjoyan Z.H. Fujise K. J. Biol. Chem. 2002; 277: 37430-37438Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Together with our observation of interactions between Mcl-1 and tankyrase 1, these findings suggest an important role of Mcl-1 in the regulation of diverse nuclear events including cell cycle regulation and telomere elongation. In conclusion, the observed interactions between Mcl-1 proteins and tankyrase 1 represent a novel mechanism for the regulation of the apoptosis function of Mcl-1 proteins. Because Mcl-1 could also regulate the function of tankyrase 1 and other nuclear proteins, Mcl-1 could play an important role in the coordinated regulation of cell survival, proliferation, and immortalization. Phylogenetically conserved Bcl-2 family proteins play a pivotal role in the regulation of apoptosis from virus to human (1Adams J.M. Cory S. Science. 1998; 281: 1322-1326Crossref PubMed Scopus (4780) Google Scholar). Members of the Bcl-2 family consist of antiapoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w, and proapoptotic proteins such as BAD, Bax, BOD, and Bok. It has been proposed that anti- and proapoptotic Bcl-2 proteins regulate cell death by binding to each other and forming heterodimers (2Yang E. Zha J. Jockel J. Boise L.H. Thompson C.B. Korsmeyer S.J. Cell. 1995; 80: 285-291Abstract Full Text PDF PubMed Scopus (1883) Google Scholar). A delicate balance between anti- and proapoptotic Bcl-2 family members exists in each cell and the relative concentration of these two groups of proteins determines whether the cell survives or undergoes apoptosis. Myeloid cell leukemia-1(Mcl-1) 1The abbreviations used are: Mcl-1, myeloid cell leukemia-1; BH domain, Bcl-2 homology domain; Mcl-1L, Mcl-1 long; Mcl-1S, Mcl-1 short; TRF1, telomeric repeat binding factor 1; CHO, Chinese hamster ovary; HA, hemagglutinin; PARP, poly(adenosine diphosphate ribose) polymerase; IRAP, insulin-responsive aminopeptidase 1The abbreviations used are: Mcl-1, myeloid cell leukemia-1; BH domain, Bcl-2 homology domain; Mcl-1L, Mcl-1 long; Mcl-1S, Mcl-1 short; TRF1, telomeric repeat binding factor 1; CHO, Chinese hamster ovary; HA, hemagglutinin; PARP, poly(adenosine diphosphate ribose) polymerase; IRAP, insulin-responsive aminopeptidase is a Bcl-2 family protein and was originally cloned as a differentiation-induced early gene that was activated in a human myeloblastic leukemia cell line (3Kozopas K.M. Yang T. Buchan H.L. Zhou P. Craig R.W. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3516-3520Crossref PubMed Scopus (873) Google Scholar). Mcl-1 is expressed in a wide variety of tissues and cells including neoplastic ones (3Kozopas K.M. Yang T. Buchan H.L. Zhou P. Craig R.W. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3516-3520Crossref PubMed Scopus (873) Google Scholar, 4Krajewski S. Bodrug S. Krajewska M. Shabaik A. Gascoyne R. Berean K. Reed J.C. Am. J. Pathol. 1995; 146: 1309-1319PubMed Google Scholar, 5Yang T. Kozopas K.M. Craig R.W. J. Cell Biol. 1995; 128: 1173-1184Crossref PubMed Scopus (270) Google Scholar). We and others recently identified a short splicing variant of Mcl-1 short (Mcl-1S) and designated the known Mcl-1 as Mcl-1 long (Mcl-1L) (6Bae J. Leo C.P. Hsu S.Y. Hsueh A.J. J. Biol. Chem. 2000; 275: 25255-25261Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 7Bingle C.D. Craig R.W. Swales B.M. Singleton V. Zhou P. Whyte M.K. J. Biol. Chem. 2000; 275: 22136-22146Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). Mcl-1L protein exhibits antiapoptotic activity and possesses the BH (Bcl-2 homology) 1, BH2, BH3, and transmembrane domains found in the related Bcl-2 proteins (3Kozopas K.M. Yang T. Buchan H.L. Zhou P. Craig R.W. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3516-3520Crossref PubMed Scopus (873) Google Scholar, 5Yang T. Kozopas K.M. Craig R.W. J. Cell Biol. 1995; 128: 1173-1184Crossref PubMed Scopus (270) Google Scholar, 8Zhou P. Qian L. Bieszczad C.K. Noelle R. Binder M. Levy N.B. Craig R.W. Blood. 1998; 92: 3226-3239Crossref PubMed Google Scholar). In contrast, Mcl-1S is a BH3 domain-only proapoptotic protein that heterodimerizes with Mcl-1L (6Bae J. Leo C.P. Hsu S.Y. Hsueh A.J. J. Biol. Chem. 2000; 275: 25255-25261Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). Although both Mcl-1L and Mcl-1S proteins contain BH domains found in other Bcl-2 family proteins, they are distinguished by their unusually long N-terminal sequences containing PEST (proline, glutamic acid, serine, and threonine) motifs, four pairs of arginine residues, and alanine- and glycine-rich regions. In addition, the tissue expression pattern of the Mcl-1 protein is different from that of Bcl-2 suggesting a unique role for Mcl-1 in apoptosis regulation (4Krajewski S. Bodrug S. Krajewska M. Shabaik A. Gascoyne R. Berean K. Reed J.C. Am. J. Pathol. 1995; 146: 1309-1319PubMed Google Scholar, 5Yang T. Kozopas K.M. Craig R.W. J. Cell Biol. 1995; 128: 1173-1184Crossref PubMed Scopus (270) Google Scholar). Tankyrase 1 (TRF1-interacting,ankyrin-elated ADP-ribose polymerase 1) was originally isolated based on its binding to TRF1 (telomeric repeat bindingfactor-1) and contains the HPS (homopolymeric runs of histidine, proline, and serine) sequence, 24 ankyrin repeats, SAM (sterile α-motif), and the catalytic domain of poly(adenosine diphosphate-ribose) polymerase (PARP) (9Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (895) Google Scholar). Previous studies have shown that tankyrase 1 promotes telomere elongation in human cells by inhibiting TRF1 through its poly(ADP-ribosyl)ation by tankyrase 1 (9Smith S. Giriat I. Schmitt A. de Lange T. Science. 1998; 282: 1484-1487Crossref PubMed Scopus (895) Google Scholar, 10Smith S. de Lange T. Curr. Biol. 2000; 10: 1299-1302Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar). In addition, tankyrase 1 poly(ADP-ribosyl)atesinsulin-responsive aminopeptidase (IRAP), a resident protein of GLUT4 vesicles, and insulin stimulates the PARP activity of tankyrase 1 through its phosphorylation by mitogen-activated protein kinase (11Chi N.W. Lodish H.F. J. Biol. Chem. 2000; 275: 38437-38444Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). Recently, tankyrase 1 also has been shown to poly(ADP-ribosyl)ate TAB182 (tankyrase-binding protein of182-kDa protein) (12Seimiya H. Smith S. J. Biol. Chem. 2002; 277: 14116-14126Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). ADP-ribosylation is a post-translational modification mechanism that usually results in a loss of protein activity presumably by enhancing protein turnover (13Althaus F.R. Richter C. Mol. Biol. Biochem. Biophys. 1987; 37: 1-237PubMed Google Scholar, 14Burkle A. Biogerontology. 2000; 1: 41-46Crossref PubMed Scopus (35) Google Scholar, 15de Murcia G. Schreiber V. Molinete M. Saulier B. Poch O. Masson M. Niedergang C. Menissier de Murcia J. Mol. Cell. Biochem. 1994; 138: 15-24Crossref PubMed Scopus (186) Google Scholar, 16D'Amours D. Desnoyers S. D'Silva I. Poirier G.G. Biochem. J. 1999; 342: 249-268Crossref PubMed Scopus (0) Google Scholar). However, little information is available regarding the physiological function(s) of tankyrase 1 other than as a PARP enzyme. In the present study, we found tankyrase 1 as a specific-binding pr" @default.
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• W2005477432 title "Tankyrase 1 Interacts with Mcl-1 Proteins and Inhibits Their Regulation of Apoptosis" @default.
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