- Research article
- Open Access
Importin alpha binding and nuclear localization of PARP-2 is dependent on lysine 36, which is located within a predicted classical NLS
- Sandra S Haenni†1,
- Matthias Altmeyer†1,
- Paul O Hassa†1, 2,
- Taras Valovka1, 3,
- Monika Fey1 and
- Michael O Hottiger1Email author
© Haenni et al; licensee BioMed Central Ltd. 2008
Received: 19 November 2007
Accepted: 21 July 2008
Published: 21 July 2008
The enzymes responsible for the synthesis of poly-ADP-ribose are named poly-ADP-ribose polymerases (PARP). PARP-2 is a nuclear protein, which regulates a variety of cellular functions that are mainly controlled by protein-protein interactions. A previously described non-conventional bipartite nuclear localization sequence (NLS) lies in the amino-terminal DNA binding domain of PARP-2 between amino acids 1–69; however, this targeting sequence has not been experimentally examined or validated.
Using a site-directed mutagenesis approach, we found that lysines 19 and 20, located within a previously described bipartite NLS, are not required for nuclear localization of PARP-2. In contrast, lysine 36, which is located within a predicted classical monopartite NLS, was required for PARP-2 nuclear localization. While wild type PARP-2 interacted with importin α3 and to a very weak extent with importin α1 and importin α5, the mutant PARP-2 (K36R) did not interact with importin α3, providing a molecular explanation why PARP-2 (K36R) is not targeted to the nucleus.
Our results provide strong evidence that lysine 36 of PARP-2 is a critical residue for proper nuclear targeting of PARP-2 and consequently for the execution of its biological functions.
Poly-ADP-ribosylation reactions occur both in multi- and unicellular organisms and play a major role in a wide range of biological processes, such as maintenance of genomic stability, transcriptional regulation and cell death (reviewed in [1, 2]). The enzyme responsible for the synthesis of poly-ADP-ribose was named poly-ADP-ribose polymerase (PARP) (reviewed in [1, 2]). For a long time, PARP-1 was thought to be the only enzyme with poly-ADP-ribosylation activity in mammalian cells; however, primary cells derived from parp-1 knockout mice can still synthesize poly-ADP-ribose polymers after DNA damage . This led to the identification of five novel poly-ADP-ribosylating enzymes, indicating that PARP-1 belongs to a family of at least six members ([4–6] and reviewed in [1, 2]). PARP-2 and PARP-1 can homo- and heterodimerize and display partially redundant functions as indicated by the embryonic lethality of the parp1-parp2-double gene disruption ( and reviewed in ).
Mouse PARP-2 was described as a 66 kDa nuclear protein with poly-ADP-ribosylating activity . The amino-terminal region of PARP-2 (aa 1–90), containing the DNA binding SAP domain, has no significant homology with any other PARP . However, it is rich in basic amino acids (27% Lys or Arg), which are likely to be involved in DNA binding (reviewed in ). On the other hand, these basic residues could be involved in the nuclear and/or nucleolar targeting of the protein . Previous studies suggested that the nuclear localization signal (NLS) of mPARP-2 is indeed located in the amino-terminal part between aa 1–69 of the protein [9, 11]. Meder et al. postulated a bipartite NLS for PARP-2, but did not provide further experimental evidences to support their hypothesis . Interestingly, the amino-terminal region of human and mouse PARP-2 shows higher sequence variability compared to the highly conserved carboxy-terminal catalytic region (62% identity between the amino-terminus of mPARP-2 and hPARP-2). In cells, PARP-2 has been described to regulate different processes via protein-protein interactions mediated by its amino-terminal domain (aa 1–208; reviewed in ).
Karyopherins, including both importins and exportins, consitute a conserved family of mobile targeting receptors that mediate the bidirectional trafficking of macromolecules across the nuclear envelope [12, 13]. Most karyopherins interact directly with cargo molecules that contain nuclear import and export signals. However, importin α functions as an adaptor that links classical NLS (cNLS)-containing proteins to importin β, which, in turn, docks the ternary complex at the nuclear-pore complex (NPC). The importin α/β heterodimer is predicted to target hundreds of proteins to the NPC and facilitate their translocation across the nuclear envelope . The importin α gene family has undergone considerable expansion during the course of eukaryotic evolution. Whereas the yeast S. cerevisiae genome encodes a single importin α, the human genome encodes six genes that fall into three phylogenetically distinct groups .
The nuclear targeting signal in the simian virus 40 (SV40) large T antigen was characterized more than 20 years ago [16, 17]. Since then, several pathways for nucleocytoplasmic transport have been described, of which the classical nuclear import pathway is the best characterized. cNLSs are typified by either a single cluster of basic amino acids (monopartite NLS) or two clusters of basic amino acids separated by a 10–12 amino acid linker (bipartite NLS). The SV40 large T antigen (PKKKRKV) and nucleoplasmin (KRPAATKKAGQAKKKK) cNLSs are the prototypic monopartite and bipartite cNLS [18, 19]. Through alanine scanning of the Myc, monopartite SV40, and artificial bipartite SV40 cNLS, Hodel and colleagues found that the binding affinity of a cNLS for importin measured in vitro correlated with the steady state nuclear accumulation and import rate of the corresponding cNLS cargo in vivo [20, 21].
Here, we demonstrate that lysine 36 in the DNA binding domain (DBD) of PARP-2, which lies within a predicted cNLS motif, is required for complex formation with the importin proteins and subsequent nuclear import of PARP-2.
Lysine 36 and/or lysine 37 of PARP-2 are required for nuclear translocation of PARP-2
Leptomycin B does not change cellular localization of PARP-2 mutant K36/37R
Lysine 36 but not lysine 37 of PARP-2 is required for nuclear localization of PARP-2
Lysine 36 is important for binding to importin α3
PARP-2 regulates different cellular functions. Here, we provide both biochemical and functional evidence that substitution of lysine residue 36 efficiently inhibits localization of PARP-2 to the nucleus. Functional analyses revealed that lysine 36 is important for complex formation with importin α3.
Lysine residues are central components of classical NLS motifs (reviewed by ) as their positive charge mediates the interaction with importin receptors . Here we provide evidence that K36 of PARP-2 is an important residue required for the nuclear translocation of PARP-2 and for complex formation with importin α3, as mutation of this residue was sufficient to disrupt association with the import machinery and subsequently alter PARP-2 nuclear localization. Interestingly, lysine 36 is conserved between mouse and human PARP-2, suggesting that the described findings might also apply for the human counterpart. Together, our data indicate that the nuclear import of human and murine PARP-2 is mediated by a conserved classical monopartite NLS but not through a bipartite NLS as previously proposed .
The formation of the importin-α/β-cNLS cargo ternary complex is the first step in the nuclear transport of hundreds of different nuclear proteins, and, as such, is tightly regulated . The relationship of importin α/β with its cNLS cargo is by necessity bipolar, because it forms highly selective and tight complexes in the cytoplasm and then switches to an extremely low affinity state in the nucleus to release the cargo. When importin α is not bound to importin β, an autoinhibitory sequence within the amino-terminal domain apparently interacts with the NLS-binding pocket . This interaction is not exceptionally strong because cNLS cargos can still bind to importin α in the absence of importin β, albeit with significantly lower affinity. The order of importin α binding to cNLS cargo and importin β is not known. The observed lack of importin α3 binding by the PARP-2 mutant (K36R) clearly indicates that this lysine is required for the interaction with importin α and subsequently for nuclear translocation.
Recently, it has become evident that importin α receptors have independent roles in the assembly of macromolecular structures. Genetic analyses of yeast importin α mutants identified several alleles that confer defects in chromosome and nuclear segregation, altered mitotic spindle structure and deficits in the ubiquitin-mediated protein degradation pathway [28–31]. Mechanistic studies on the roles of importin αs in mitosis, spindle assembly and nuclear envelope biogenesis point more directly to activities which are independent of the housekeeping roles of importin α in nuclear transport. The observed interaction of PARP-2 with importin α might thus not only be important for its nuclear translocation but might have an additional physiological function in maintaining the integrity of the genome. Inactivation of the parp-2 gene in mice revealed that PARP-2 may be involved in the surveillance and maintenance of genome integrity, indicated by the sensitivity of these mice to ionizing radiation .
Others have reported that PARP-2 is enriched within the whole nucleolus and partially colocalizes with the nucleolar factor nucleophosmin/B23 . Using partial cDNA fragments in-frame with the carboxy-terminus of EGFP the authors described a putative nuclear localization signal and a nucleolar localization signal within the amino-terminal domain of PARP-2 (aa 1–69). Our studies revealed that overexpressed PARP-2 was only found equally distributed in the nucleus, but in contradiction to this previous report, was never observed in the nucleolus of the cell. This discrepancy could be explained by the different experimental approaches used. Meder et al. studied the nucleolar localization of PARP-2 with GFP-fusion proteins, while our studies were performed with non-GFP tagged full-length proteins. Remarkably, PARP-1 nucleolar accumulation was not observed when endogenous or overexpressed PARP-1 localization was analyzed by a conventional immunofluorecence protocol as described in Methods using specific anti-PARP-1 antibodies (data not shown). Only applying the fixation protocol described in Meder et al. , which led to the decomposition of the cell and loss of cytoplasm, revealed the reported nucleolar staining of PARP-1, suggesting that the fixation protocol influences the nucleolar localization of proteins or the detection of proteins within the nucleolus.
Recently, acetylation of lysine residues by histone acetyltransferases (HATs), such as p300/CBP (CREB-binding protein) and PCAF (p300/CBP-associated factor), has been proposed as a new mechanism for modulating cellular localization [32–36]. HATs trigger the transfer of an acetyl group from acetyl coenzyme A to the epsilon-amino group of a lysine residue not only on core histones but also on about 40 transcription factors and on more than 30 other proteins . We recently published that both lysines 36 and 37 of PARP-2 are indeed acetylated in vitro and in vivo and that acetylation influences both DNA binding and auto-ADP-ribosylation of PARP-2 .
Taken together, our results provide evidence that PARP-2 accumulates in the nucleus and that lysine 36, which is located within a monopartite cNLS, is important for binding of PARP-2 to importin α3 and for the nuclear translocation of PARP-2.
Mammalian expression vectors for wild type PARP-2 and all mutants used in this study were obtained by cloning the corresponding PCR products into pphCMV-HA. PARP-2 mutants were generated by a site directed mutagenesis procedure and confirmed by sequencing. Bacterial expression vectors for human GST-importins α1, α3, α5 and α7 were provided by Dr. Riku Fagerlund (Departments of Viral Diseases and Immunology and Epidemiology and Health Promotion, National Public Health Institute, FIN-00300, Helsinki, Finland, ).
Expression and purification of recombinant proteins
GST-tagged importins were expressed in E. coli strain BL21-D3-Gold. All purified proteins were analyzed by Coomassie staining and confirmed by western blot analysis using the corresponding antibodies.
Cell culture and transient transfections, treatment with LMB and immunofluorescence
HEK293T cells were grown in Hepes-buffered DMEM-Glutamax-I (Invitrogen) containing 4.5 g/L glucose and 10% FCS US/certified (Invitrogen) and supplemented with 50 U/ml penicillin, 50 μg/ml streptomycin (Invitrogen) and MEM non-essential amino acids (MEM NEAA, Invitrogen). Cells were transfected using calcium phosphate procedures as described in . For the experiments with Leptomycin B (LMB), cells were treated with a final concentration of 20 ng/ml LMB for 4–16 hrs. For detection of overexpressed proteins by immunofluorescence, HEK293T cells were fixed for 10 minutes in ice-cold 100% methanol in the absence of detergents and unspecific binding sites were blocked with 2% BSA/0.1% Triton X-100 prior to staining with primary and FITC-conjugated secondary antibodies in the presence of 2% BSA/0.1% Triton X-100 according to the manufacturer's protocol (Covance) using confocal (Leica SP2, 40× oil-immersion, NA 1.25, zoom-in) or standard fluorescence microscopy (Olympus Mx51, 100× oil-immersion, NA 1.3).
Western blot analysis and antibodies
Western blot analyses were performed as described previously . Anti-myc-9E10 (sc-2027) antibodies were obtained from Santa Cruz Biotechnology, anti-HA (MMS-101P) was obtained from COVANCE. Antibodies against mouse PARP-1 and PARP-2 were generated in house (the generation of antibodies against mouse PARP-1 has been described previously [42, 43]).
In vitro interaction and GST pull-down assays
Purified recombinant proteins fused to GST were bound to Glutathione Sepharose 4B according to the manufacturer's protocols (Amersham Biosciences). GST pull-down assays were performed as described previously [41, 42]. GST pull-down-buffers contain: 50 mM Tris [pH 8.0], 150 mM NaCl, 0.5% NP-40, 0.5 mM DTT, 1 mM PMSF, 100 μM bestatin, 3 μM pepstatin A, 5 μM leupeptin. Bound proteins were dissolved by SDS PAGE and subsequently analyzed by western blot.
We are grateful to Dr. Riku Fagerlund (Departments of Viral Diseases and Immunology and Epidemiology and Health Promotion, National Public Health Institute, FIN-00300, Helsinki, Finland) for the importin expression vectors. Leptomycin B was a very generous gift of Dr. Minoru Yoshida (University of Tokyo, Japan). We would also like to thank the members of the Institute of Veterinary Biochemistry and Molecular Biology (University of Zurich, Switzerland) for their helpful advice and comments. This work was supported in part by the Swiss National Science Foundation Grant 31-109315.05 to S.S.H., M.A. and P.O.H.; T.V., M.F. and M.O.H. were supported by the Kanton of Zurich.
- Hassa PO, Hottiger MO: The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci. 2008, 13: 3046-3082. 10.2741/2909.View ArticlePubMedGoogle Scholar
- Hassa PO, Haenni SS, Elser M, Hottiger MO: Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going?. Microbiol Mol Biol Rev. 2006, 70: 789-829. 10.1128/MMBR.00040-05.PubMed CentralView ArticlePubMedGoogle Scholar
- Shieh WM, Ame JC, Wilson MV, Wang ZQ, Koh DW, Jacobson MK, Jacobson EL: Poly(ADP-ribose) polymerase null mouse cells synthesize ADP-ribose polymers. J Biol Chem. 1998, 273: 30069-30072. 10.1074/jbc.273.46.30069.View ArticlePubMedGoogle Scholar
- Marsischky GT, Wilson BA, Collier RJ: Role of glutamic acid 988 of human poly-ADP-ribose polymerase in polymer formation. Evidence for active site similarities to the ADP-ribosylating toxins. J Biol Chem. 1995, 270: 3247-3254. 10.1074/jbc.270.7.3247.View ArticlePubMedGoogle Scholar
- Rolli V, O'Farrell M, Menissier-de Murcia J, de Murcia G: Random mutagenesis of the poly(ADP-ribose) polymerase catalytic domain reveals amino acids involved in polymer branching. Biochemistry. 1997, 36: 12147-12154. 10.1021/bi971055p.View ArticlePubMedGoogle Scholar
- Ruf A, Rolli V, de Murcia G, Schulz GE: The mechanism of the elongation and branching reaction of poly(ADP-ribose) polymerase as derived from crystal structures and mutagenesis. J Mol Biol. 1998, 278: 57-65. 10.1006/jmbi.1998.1673.View ArticlePubMedGoogle Scholar
- Menissier de Murcia J, Ricoul M, Tartier L, Niedergang C, Huber A, Dantzer F, Schreiber V, Ame JC, Dierich A, LeMeur M, Sabatier L, Chambon P, de Murcia G: Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. Embo J. 2003, 22: 2255-2263. 10.1093/emboj/cdg206.PubMed CentralView ArticlePubMedGoogle Scholar
- Schreiber V, Dantzer F, Ame JC, de Murcia G: Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol. 2006, 7: 517-528. 10.1038/nrm1963.View ArticlePubMedGoogle Scholar
- Ame JC, Rolli V, Schreiber V, Niedergang C, Apiou F, Decker P, Muller S, Hoger T, Menissier-de Murcia J, de Murcia G: PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem. 1999, 274: 17860-17868. 10.1074/jbc.274.25.17860.View ArticlePubMedGoogle Scholar
- Dang CV, Lee WM: Nuclear and nucleolar targeting sequences of c-erb-A, c-myb, N-myc, p53, HSP70, and HIV tat proteins. J Biol Chem. 1989, 264: 18019-18023.PubMedGoogle Scholar
- Meder VS, Boeglin M, de Murcia G, Schreiber V: PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli. J Cell Sci. 2005, 118: 211-222. 10.1242/jcs.01606.View ArticlePubMedGoogle Scholar
- Fried H, Kutay U: Nucleocytoplasmic transport: taking an inventory. Cell Mol Life Sci. 2003, 60: 1659-1688. 10.1007/s00018-003-3070-3.View ArticlePubMedGoogle Scholar
- Macara IG: Transport into and out of the nucleus. Microbiol Mol Biol Rev. 2001, 65: 570-594. 10.1128/MMBR.65.4.570-594.2001. table of contents.PubMed CentralView ArticlePubMedGoogle Scholar
- Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH: Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem. 2007, 282: 5101-5105. 10.1074/jbc.R600026200.PubMed CentralView ArticlePubMedGoogle Scholar
- Goldfarb DS, Corbett AH, Mason DA, Harreman MT, Adam SA: Importin alpha: a multipurpose nuclear-transport receptor. Trends Cell Biol. 2004, 14: 505-514. 10.1016/j.tcb.2004.07.016.View ArticlePubMedGoogle Scholar
- Kalderon D, Richardson WD, Markham AF, Smith AE: Sequence requirements for nuclear location of simian virus 40 large-T antigen. Nature. 1984, 311: 33-38. 10.1038/311033a0.View ArticlePubMedGoogle Scholar
- Kalderon D, Roberts BL, Richardson WD, Smith AE: A short amino acid sequence able to specify nuclear location. Cell. 1984, 39: 499-509. 10.1016/0092-8674(84)90457-4.View ArticlePubMedGoogle Scholar
- Robbins J, Dilworth SM, Laskey RA, Dingwall C: Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: identification of a class of bipartite nuclear targeting sequence. Cell. 1991, 64: 615-623. 10.1016/0092-8674(91)90245-T.View ArticlePubMedGoogle Scholar
- Dingwall C, Laskey RA: Nuclear targeting sequences – a consensus?. Trends Biochem Sci. 1991, 16: 478-481. 10.1016/0968-0004(91)90184-W.View ArticlePubMedGoogle Scholar
- Hodel MR, Corbett AH, Hodel AE: Dissection of a nuclear localization signal. J Biol Chem. 2001, 276: 1317-1325. 10.1074/jbc.M008522200.View ArticlePubMedGoogle Scholar
- Hodel AE, Harreman MT, Pulliam KF, Harben ME, Holmes JS, Hodel MR, Berland KM, Corbett AH: Nuclear localization signal receptor affinity correlates with in vivo localization in Saccharomyces cerevisiae. J Biol Chem. 2006, 281: 23545-23556. 10.1074/jbc.M601718200.View ArticlePubMedGoogle Scholar
- Fornerod M, Ohno M, Yoshida M, Mattaj IW: CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997, 90: 1051-1060. 10.1016/S0092-8674(00)80371-2.View ArticlePubMedGoogle Scholar
- Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M, Yanagida M, Nishida E: CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature. 1997, 390: 308-311. 10.1038/36894.View ArticlePubMedGoogle Scholar
- Wolff B, Sanglier JJ, Wang Y: Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem Biol. 1997, 4: 139-147. 10.1016/S1074-5521(97)90257-X.View ArticlePubMedGoogle Scholar
- Poon IK, Jans DA: Regulation of nuclear transport: central role in development and transformation?. Traffic. 2005, 6: 173-186. 10.1111/j.1600-0854.2005.00268.x.View ArticlePubMedGoogle Scholar
- Conti E, Uy M, Leighton L, Blobel G, Kuriyan J: Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha. Cell. 1998, 94: 193-204. 10.1016/S0092-8674(00)81419-1.View ArticlePubMedGoogle Scholar
- Kobe B: Autoinhibition by an internal nuclear localization signal revealed by the crystal structure of mammalian importin alpha. Nat Struct Biol. 1999, 6: 388-397. 10.1038/7625.View ArticlePubMedGoogle Scholar
- Loeb JD, Schlenstedt G, Pellman D, Kornitzer D, Silver PA, Fink GR: The yeast nuclear import receptor is required for mitosis. Proc Natl Acad Sci USA. 1995, 92: 7647-7651. 10.1073/pnas.92.17.7647.PubMed CentralView ArticlePubMedGoogle Scholar
- Kussel P, Frasch M: Yeast Srp1, a nuclear protein related to Drosophila and mouse pendulin, is required for normal migration, division, and integrity of nuclei during mitosis. Mol Gen Genet. 1995, 248: 351-363. 10.1007/BF02191602.View ArticlePubMedGoogle Scholar
- Tabb MM, Tongaonkar P, Vu L, Nomura M: Evidence for separable functions of Srp1p, the yeast homolog of importin alpha (Karyopherin alpha): role for Srp1p and Sts1p in protein degradation. Mol Cell Biol. 2000, 20: 6062-6073. 10.1128/MCB.20.16.6062-6073.2000.PubMed CentralView ArticlePubMedGoogle Scholar
- Yano R, Oakes ML, Tabb MM, Nomura M: Yeast Srp1p has homology to armadillo/plakoglobin/beta-catenin and participates in apparently multiple nuclear functions including the maintenance of the nucleolar structure. Proc Natl Acad Sci USA. 1994, 91: 6880-6884. 10.1073/pnas.91.15.6880.PubMed CentralView ArticlePubMedGoogle Scholar
- Bannister AJ, Miska EA, Gorlich D, Kouzarides T: Acetylation of importin-alpha nuclear import factors by CBP/p300. Curr Biol. 2000, 10: 467-470. 10.1016/S0960-9822(00)00445-0.View ArticlePubMedGoogle Scholar
- Soutoglou E, Katrakili N, Talianidis I: Acetylation regulates transcription factor activity at multiple levels. Mol Cell. 2000, 5: 745-751. 10.1016/S1097-2765(00)80253-1.View ArticlePubMedGoogle Scholar
- Spilianakis C, Papamatheakis J, Kretsovali A: Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Mol Cell Biol. 2000, 20: 8489-8498. 10.1128/MCB.20.22.8489-8498.2000.PubMed CentralView ArticlePubMedGoogle Scholar
- Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi ME: Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. Embo J. 2003, 22: 5551-5560. 10.1093/emboj/cdg516.PubMed CentralView ArticlePubMedGoogle Scholar
- Santos-Rosa H, Valls E, Kouzarides T, Martinez-Balbas M: Mechanisms of P/CAF auto-acetylation. Nucleic Acids Res. 2003, 31: 4285-4292. 10.1093/nar/gkg655.PubMed CentralView ArticlePubMedGoogle Scholar
- Yang XJ: The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 2004, 32: 959-976. 10.1093/nar/gkh252.PubMed CentralView ArticlePubMedGoogle Scholar
- Haenni SS, Hassa PO, Altmeyer M, Fey M, Imhof R, Hottiger MO: Identification of lysines 36 and 37 of PARP-2 as targets for acetylation and auto-ADP-ribosylation. Int J Biochem Cell Biol. 2008Google Scholar
- Melen K, Fagerlund R, Franke J, Kohler M, Kinnunen L, Julkunen I: Importin alpha nuclear localization signal binding sites for STAT1, STAT2, and influenza A virus nucleoprotein. J Biol Chem. 2003, 278: 28193-28200. 10.1074/jbc.M303571200.View ArticlePubMedGoogle Scholar
- Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ: Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. Science. 1997, 275: 523-527. 10.1126/science.275.5299.523.View ArticlePubMedGoogle Scholar
- Hassa PO, Buerki C, Lombardi C, Imhof R, Hottiger MO: Transcriptional coactivation of nuclear factor-kappaB-dependent gene expression by p300 is regulated by poly(ADP)-ribose polymerase-1. J Biol Chem. 2003, 278: 45145-45153. 10.1074/jbc.M307957200.View ArticlePubMedGoogle Scholar
- Hassa PO, Haenni SS, Buerki C, Meier NI, Lane WS, Owen H, Gersbach M, Imhof R, Hottiger MO: Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription. J Biol Chem. 2005, 280: 40450-40464. 10.1074/jbc.M507553200.View ArticlePubMedGoogle Scholar
- Petrilli V, Herceg Z, Hassa PO, Patel NS, Di Paola R, Cortes U, Dugo L, Filipe HM, Thiemermann C, Hottiger MO, Cuzzocrea S, Wang ZQ: Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice. J Clin Invest. 2004, 114: 1072-1081.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.