Advertisement

The cdk5 Kinase Regulates the STAT3 Transcription Factor to Prevent DNA Damage upon Topoisomerase I Inhibition*

Open AccessPublished:June 01, 2010DOI:https://doi.org/10.1074/jbc.M109.092304
      The STAT3 transcription factors are cytoplasmic proteins that induce gene activation in response to growth factor stimulation. Following tyrosine phosphorylation, STAT3 proteins dimerize, translocate to the nucleus, and activate specific target genes involved in cell-cycle progression. Despite its importance in cancer cells, the molecular mechanisms by which this protein is regulated in response to DNA damage remain to be characterized. In this study, we show that STAT3 is activated in response to topoisomerase I inhibition. Following treatment, STAT3 is phosphorylated on its C-terminal serine 727 residue but not on its tyrosine 705 site. We also show that topoisomerase I inhibition induced the up-regulation of the cdk5 kinase, a protein initially described in neuronal stress responses. In co-immunoprecipitations, cdk5 was found to associate with STAT3, and pulldown experiments indicated that it associates with the C-terminal activation domain of STAT3 upon DNA damage. Importantly, the cdk5-STAT3 pathway reduced DNA damage in response to topoisomerase I inhibition through the up-regulation of Eme1, an endonuclease involved in DNA repair. ChIP experiments indicated that STAT3 can be found associated with the Eme1 promoter when phosphorylated only on its serine 727 residue and not on tyrosine 705. We therefore propose that the cdk5-STAT3 oncogenic pathway plays an important role in the expression of DNA repair genes and that these proteins could be used as predictive markers of tumors that will fail to respond to chemotherapy.

      Introduction

      Signal transducer and activator of transcription 3 (STAT3)
      The abbreviations used are: STAT3
      signal transducers and activators of transcription 3
      ChIP
      chromatin immunoprecipitation
      CBP
      CREB-binding protein
      cdk
      cyclin-dependent kinase
      siRNA
      small interference RNA
      PBS
      phosphate-buffered saline
      RT
      reverse transcription
      IL-6
      interleukin-6
      FACS
      fluorescent-activated cell sorting.
      proteins are cytoplasmic transcription factors that translocate into the nucleus following growth factor stimulation. In contrast to normal cells where its phosphorylation is only transient, constitutive activation of STAT3 has been reported in several primary cancers and tumor cell lines (
      • Bromberg J.
      ,
      • Yu H.
      • Jove R.
      ,
      • Levy D.E.
      • Lee C.K.
      ). This abnormal activation is due to oncogenic kinases such as epidermal growth factor receptor, Her2/Neu, src, or bcr-abl, which induce STAT3 activation through phosphorylation of its tyrosine 705 residue (
      • Bromberg J.F.
      • Horvath C.M.
      • Besser D.
      • Lathem W.W.
      • Darnell Jr., J.E.
      ). This phosphorylation allows the nuclear translocation and DNA binding of the STAT3 dimer and the up-regulation of several genes involved in cell-cycle and cell survival such as cyclin D1, Myc, or bclxl. The up-regulation of these cancer genes mediates the oncogenic activity of STAT3 and its ability to transform cells (
      • Bromberg J.F.
      • Wrzeszczynska M.H.
      • Devgan G.
      • Zhao Y.
      • Pestell R.G.
      • Albanese C.
      • Darnell Jr., J.E.
      ).
      A second phosphorylation occurs on the serine 727 residue of the C-terminal activation domain. It has been proposed that this phosphorylation is necessary for maximal gene activation, because its mutation prevents STAT3 transcriptional function (
      • Wen Z.
      • Zhong Z.
      • Darnell Jr., J.E.
      ). It is believed that this modification favors the recruitment of transcriptional cofactors such as CBP, NcoA, or P-Tefb that binds to the C-terminal domain of the transcription factor (
      • Giraud S.
      • Bienvenu F.
      • Avril S.
      • Gascan H.
      • Heery D.M.
      • Coqueret O.
      ,
      • Giraud S.
      • Hurlstone A.
      • Avril S.
      • Coqueret O.
      ,
      • Paulson M.
      • Pisharody S.
      • Pan L.
      • Guadagno S.
      • Mui A.L.
      • Levy D.E.
      ,
      • Nakashima K.
      • Yanagisawa M.
      • Arakawa H.
      • Kimura N.
      • Hisatsune T.
      • Kawabata M.
      • Miyazono K.
      • Taga T.
      ). However, it remains to be determined if the association of STAT3 with its coactivators is a direct consequence of Ser-727 phosphorylation.
      Although it was initially believed that the tyrosine phosphorylation is essential for STAT3 activity, several groups have recently reported that specific forms of the transcription factor, which are only phosphorylated on its Ser-727 residue, can induce gene activation. In prostate cancer, Ser-727 phosphorylation is sufficient to activate STAT3 and drive tumorigenesis in the absence of tyrosine 705 activation (
      • Qin H.R.
      • Kim H.J.
      • Kim J.Y.
      • Hurt E.M.
      • Klarmann G.J.
      • Kawasaki B.T.
      • Duhagon Serrat M.A.
      • Farrar W.L.
      ). Elegant results have shown that tyrosine 705 mutants can associate with NF-κB and induce the expression of genes such as mras or met, which are likely to play an important role in cell transformation by STAT3 (
      • Yang J.
      • Chatterjee-Kishore M.
      • Staugaitis S.M.
      • Nguyen H.
      • Schlessinger K.
      • Levy D.E.
      • Stark G.R.
      ,
      • Yang J.
      • Liao X.
      • Agarwal M.K.
      • Barnes L.
      • Auron P.E.
      • Stark G.R.
      ,
      • Lee H.
      • Herrmann A.
      • Deng J.H.
      • Kujawski M.
      • Niu G.
      • Li Z.
      • Forman S.
      • Jove R.
      • Pardoll D.M.
      • Yu H.
      ). These results lead to the important conclusion that the influence of STAT3 on cell transformation can be independent of the tyrosine 705 phosphorylation and that this site should not be considered as a unique marker of STAT3 oncogenic activity.
      This conclusion also leads to the hypothesis that STAT3 can induce different transcriptional programs, depending on which sites are phosphorylated and certainly on the type of stimulation. Although STAT3 activation is well characterized in response to growth factor stimulation, little is known about its regulation in response to other stimulation such as DNA damage and chemotherapy treatment. Interestingly, several studies have suggested that an abnormal activation of this transcription factor is associated with intrinsic drug resistance (
      • Barré B.
      • Vigneron A.
      • Perkins N.
      • Roninson I.B.
      • Gamelin E.
      • Coqueret O.
      ). STAT3 expression has been associated with resistance to radiation-induced apoptosis (
      • Sano S.
      • Chan K.S.
      • Kira M.
      • Kataoka K.
      • Takagi S.
      • Tarutani M.
      • Itami S.
      • Kiguchi K.
      • Yokoi M.
      • Sugasawa K.
      • Mori T.
      • Hanaoka F.
      • Takeda J.
      • DiGiovanni J.
      ,
      • Shen Y.
      • Devgan G.
      • Darnell Jr., J.E.
      • Bromberg J.F.
      ,
      • Niu G.
      • Wright K.L.
      • Ma Y.
      • Wright G.M.
      • Huang M.
      • Irby R.
      • Briggs J.
      • Karras J.
      • Cress W.D.
      • Pardoll D.
      • Jove R.
      • Chen J.
      • Yu H.
      ), and it can also confer resistance to Fas or paclitaxel-mediated apoptosis in multiple myeloma and ovarian cancer (
      • Catlett-Falcone R.
      • Landowski T.H.
      • Oshiro M.M.
      • Turkson J.
      • Levitzki A.
      • Savino R.
      • Ciliberto G.
      • Moscinski L.
      • Fernández-Luna J.L.
      • Nuñez G.
      • Dalton W.S.
      • Jove R.
      ,
      • Duan Z.
      • Foster R.
      • Bell D.A.
      • Mahoney J.
      • Wolak K.
      • Vaidya A.
      • Hampel C.
      • Lee H.
      • Seiden M.V.
      ). Most of the time, escape to drug treatment is related to the STAT3-mediated expression of survival proteins such as bcl-xl or survivin (
      • Diaz N.
      • Minton S.
      • Cox C.
      • Bowman T.
      • Gritsko T.
      • Garcia R.
      • Eweis I.
      • Wloch M.
      • Livingston S.
      • Seijo E.
      • Cantor A.
      • Lee J.H.
      • Beam C.A.
      • Sullivan D.
      • Jove R.
      • Muro-Cacho C.A.
      ,
      • Gritsko T.
      • Williams A.
      • Turkson J.
      • Kaneko S.
      • Bowman T.
      • Huang M.
      • Nam S.
      • Eweis I.
      • Diaz N.
      • Sullivan D.
      • Yoder S.
      • Enkemann S.
      • Eschrich S.
      • Lee J.H.
      • Beam C.A.
      • Cheng J.
      • Minton S.
      • Muro-Cacho C.A.
      • Jove R.
      ). In addition, we have recently shown that the epidermal growth factor receptor-src-STAT3 pathway can prevent senescence induction (
      • Vigneron A.
      • Roninson I.B.
      • Gamelin E.
      • Coqueret O.
      ) and activate DNA repair genes (
      • Vigneron A.
      • Gamelin E.
      • Coqueret O.
      ) to confer resistance to chemotherapy treatments.
      In this study, we have further characterized the regulation of STAT3 during DNA damage. In colorectal cell lines, we have found that the transcription factor is phosphorylated on its serine 727 residue following topoisomerase I inhibition and that tyrosine 705 phosphorylation is not modified. In addition, we have also observed that this phosphorylation is due to the binding of the cdk5 kinase to the transcription factor. cdk5 is a serine/threonine kinase, which was initially characterized in postmitotic neurons. Once associated with its specific activators p35/p25, this protein plays an important role in neuronal survival, neurite outgrowth, and cytoskeletal functions (
      • Dhavan R.
      • Tsai L.H.
      ,
      • Gong X.
      • Tang X.
      • Wiedmann M.
      • Wang X.
      • Peng J.
      • Zheng D.
      • Blair L.A.
      • Marshall J.
      • Mao Z.
      ,
      • Wang C.X.
      • Song J.H.
      • Song D.K.
      • Yong V.W.
      • Shuaib A.
      • Hao C.
      ). In response to topoisomerase I inhibition, we have observed that cdk5 is activated and that it interacts with STAT3 to induce its serine phosphorylation. Cdk5 appeared to be involved in the STAT3-mediated regulation of the cyclin D1, myc, and Eme1 genes. Importantly, ChIP analysis showed that the transcription factor can be found associated with the Eme1 promoter when phosphorylated only on serine 727. We therefore propose that cdk5 regulates the STAT3-Eme1 pathway and that this is an important step in the response of colorectal tumors to topoisomerase I inhibition.

      DISCUSSION

      In this study, we have found that the STAT3 transcription factor is phosphorylated on its serine C-terminal residue but not on tyrosine 705 upon topoisomerase I inhibition. Our results indicate that this is due to the activation of the cdk5 kinase, which binds to the C-terminal of domain of the transcription factor to induce its phosphorylation. Importantly, cdk5 is involved in the down-regulation of early G1 genes such as myc and cyclin D1 and in the STAT3-mediated up-regulation of the Eme1 gene, an endonuclease involved in the processing of damaged replication forks. In light of these results, we propose that the cdk5-STAT3-Eme1 pathway plays an important role in the response to topoisomerase I inhibition and chemotherapy treatments.
      It is well known that STAT3 is activated at the G0-G1 transition following cytokine or growth factor stimulation. In this condition, the transcription factor binds to the promoter of several cell cycle genes such as myc, cyclin D1, fos, or cdc25A to induce their expression and activate progression toward S phase. Gene activation by STAT3 during the G0-G1 transition is due to the phosphorylation of STAT3 on its tyrosine residue, followed by nuclear translocation and DNA binding. The second phosphorylation of STAT3 on its serine residue allows the contact of the tyrosine-phosphorylated dimer with transcriptional cofactors such as CBP, NcoA, or Ptefb. However, this pathway is probably not the only mechanism by which STAT proteins are activated, because several results have shown that these transcription factors induce transcription in the absence of tyrosine phosphorylation. This was originally described with STAT1 when it was shown that this transcription factor can drive the expression of several genes in the absence of tyrosine phosphorylation (
      • Chatterjee-Kishore M.
      • Wright K.L.
      • Ting J.P.
      • Stark G.R.
      ). Using non-phosphorylated forms of STAT3 on its tyrosine residue, Yang et al. have shown that these mutants can induce the expression of genes such as met and mras, which certainly play an important role in the oncogenic activity of STAT3. Under these conditions, gene activation is a consequence of the formation of a STAT3-NF-κB enhanceosome that plays a key role in transformed cells (
      • Yang J.
      • Chatterjee-Kishore M.
      • Staugaitis S.M.
      • Nguyen H.
      • Schlessinger K.
      • Levy D.E.
      • Stark G.R.
      ,
      • Yang J.
      • Liao X.
      • Agarwal M.K.
      • Barnes L.
      • Auron P.E.
      • Stark G.R.
      ). Most importantly, the genes regulated by STAT3 in these conditions are normally not activated when the transcription factor is phosphorylated on its tyrosine residue. This leads to the important conclusion that the STAT3 transcriptional targets depends on its post-translational modifications.
      Importantly, using ChIP analysis, we have been able to detect STAT3 on the Eme1 promoter when phosphorylated only on its Ser-727 residue. We therefore propose that STAT3 is activated by DNA damage during the G2 phase of the cell cycle and that its serine phosphorylation allows the specific up-regulation of DNA repair genes such as the Eme1 endonuclease. Surprisingly, the role of STAT3 in the response to genotoxic treatment has not been well characterized. By contrast, it is known that both STAT1 and STAT5 are regulated following DNA damage. STAT1 is involved in the S and G2/M checkpoints and can associate with repair signaling proteins such as Chk2 and Mdc1 in response to γ-irradiation (
      • Townsend P.A.
      • Cragg M.S.
      • Davidson S.M.
      • McCormick J.
      • Barry S.
      • Lawrence K.M.
      • Knight R.A.
      • Hubank M.
      • Chen P.L.
      • Latchman D.S.
      • Stephanou A.
      ,
      • Thomas M.
      • Finnegan C.E.
      • Rogers K.M.
      • Purcell J.W.
      • Trimble A.
      • Johnston P.G.
      • Boland M.P.
      ). In addition, this transcription factor is also phosphorylated in response to topoisomerase inhibitors (
      • Thomas M.
      • Finnegan C.E.
      • Rogers K.M.
      • Purcell J.W.
      • Trimble A.
      • Johnston P.G.
      • Boland M.P.
      ). STAT5 has been shown to regulate the expression of rad51 and, importantly, this has been linked to the ability of several oncogenic kinases such as bcr-abl or tel-jak2 to induce drug resistance (
      • Slupianek A.
      • Schmutte C.
      • Tombline G.
      • Nieborowska-Skorska M.
      • Hoser G.
      • Nowicki M.O.
      • Pierce A.J.
      • Fishel R.
      • Skorski T.
      ,
      • Slupianek A.
      • Hoser G.
      • Majsterek I.
      • Bronisz A.
      • Malecki M.
      • Blasiak J.
      • Fishel R.
      • Skorski T.
      ). Interestingly, recent results also suggest that STAT3 plays an important role in the regulation of genome stability. The inactivation of the T-cell protein tyrosine phosphatase induces a constitutive activation of STAT3 probably as a consequence of replication fork stalling, and this leads to aberrant mitoses with lagging chromosomes (
      • Shields B.J.
      • Hauser C.
      • Bukczynska P.E.
      • Court N.W.
      • Tiganis T.
      ). Unfortunately, the link between STAT3 and DNA repair has not been characterized in this study, because this effect has been linked to a sustained expression of cyclin D1 during S phase. Further suggesting a link between STAT3 and DNA stability, it is well known that a direct target of STAT3, myc, can induce DNA damage and dysregulate genomic stability and DNA repair pathways (
      • Vafa O.
      • Wade M.
      • Kern S.
      • Beeche M.
      • Pandita T.K.
      • Hampton G.M.
      • Wahl G.M.
      ). In this study, we further extend these observations, showing that this transcription factor is activated by Cdk5 in response to topoisomerase I inhibitors. We speculate that this kinase allows the formation of a new STAT3 enhanceosome that would specifically regulate the expression of DNA repair genes upon genotoxic treatment. In light of recent results showing an essential role of NF-κB in the response to DNA damage (
      • Campbell K.J.
      • Witty J.M.
      • Rocha S.
      • Perkins N.D.
      ), one interesting hypothesis is that genes involved in the response to sn38 are controlled by a specific STAT3-NF-κB complex that would be activated by cdk5. It will be interesting to determine if this enhanceosome preferentially binds DNA repair genes as opposed to more conventional STAT3 targets such as myc or cdc25A.
      As a consequence of DNA repair genes regulation, our results indicate that the cdk5-STAT3 pathway reduces DNA damage in response to topoisomerase I inhibition. This suggests that these proteins might play an essential role in the resistance of cancer cells to chemotherapy. Further confirming the importance of this oncogenic cascade, recent results have shown that the cdk5-STAT3 pathway plays an essential role in thyroid carcinomas (
      • Lin H.
      • Chen M.C.
      • Chiu C.Y.
      • Song Y.M.
      • Lin S.Y.
      ). In addition, we and others have recently shown that STAT3 prevents the induction of senescence through p53-p21 inactivation (
      • Niu G.
      • Wright K.L.
      • Ma Y.
      • Wright G.M.
      • Huang M.
      • Irby R.
      • Briggs J.
      • Karras J.
      • Cress W.D.
      • Pardoll D.
      • Jove R.
      • Chen J.
      • Yu H.
      ,
      • Barré B.
      • Avril S.
      • Coqueret O.
      ,
      • Flørenes V.A.
      • Lu C.
      • Bhattacharya N.
      • Rak J.
      • Sheehan C.
      • Slingerland J.M.
      • Kerbel R.S.
      ,
      • Bienvenu F.
      • Barre B.
      • Giraud S.
      • Avril S.
      • Coqueret O.
      ). Interestingly, cdk5 is also involved in senescence programs, because this kinase regulates cell morphology through ezrin and rac1 modulation (
      • Alexander K.
      • Yang H.S.
      • Hinds P.W.
      ,
      • Yang H.S.
      • Hinds P.W.
      ). It will be interesting to determine if cdk5 is also involved in the inactivation of the p53-p21 pathway by the STAT3 oncogene during senescence induction.
      In light of this study and other results (
      • Lin H.
      • Chen M.C.
      • Chiu C.Y.
      • Song Y.M.
      • Lin S.Y.
      ), we therefore propose that cdk5 plays an important role in cell transformation by the STAT3 oncogene. Because it has been proposed that cell transformation induces an intrinsic resistance program to chemotherapy (
      • Johnstone R.W.
      • Ruefli A.A.
      • Lowe S.W.
      ), we speculate that cdk5-STAT3 provides cancer cells with intrinsic resistance capacities due to enhanced Eme1 expression and that this a corollary of cell transformation. We propose that the early detection on tumor biopsies of the cdk5-STAT3 oncogenic pathway, both of its phosphorylation status and of its target genes, will provide oncologists with a resistance profile indicative of tumors that will fail to respond to chemotherapy (
      • Barré B.
      • Vigneron A.
      • Perkins N.
      • Roninson I.B.
      • Gamelin E.
      • Coqueret O.
      ,
      • Henderson B.W.
      • Daroqui C.
      • Tracy E.
      • Vaughan L.A.
      • Loewen G.M.
      • Cooper M.T.
      • Baumann H.
      ). In addition, we also propose that STAT3 inhibitors, which are emerging as new targeted cancer therapies (
      • Yu H.
      • Jove R.
      ,
      • Henderson B.W.
      • Daroqui C.
      • Tracy E.
      • Vaughan L.A.
      • Loewen G.M.
      • Cooper M.T.
      • Baumann H.
      ,
      • Benekli M.
      • Baumann H.
      • Wetzler M.
      ) should be tested in clinical trials in combination with irinotecan to reduce DNA repair and enhance the efficiency of genotoxic treatments.

      REFERENCES

        • Bromberg J.
        J. Clin. Invest. 2002; 109: 1139-1142
        • Yu H.
        • Jove R.
        Nat. Rev. Cancer. 2004; 4: 97-105
        • Levy D.E.
        • Lee C.K.
        J. Clin. Invest. 2002; 109: 1143-1148
        • Bromberg J.F.
        • Horvath C.M.
        • Besser D.
        • Lathem W.W.
        • Darnell Jr., J.E.
        Mol. Cell. Biol. 1998; 18: 2553-2558
        • Bromberg J.F.
        • Wrzeszczynska M.H.
        • Devgan G.
        • Zhao Y.
        • Pestell R.G.
        • Albanese C.
        • Darnell Jr., J.E.
        Cell. 1999; 98: 295-303
        • Wen Z.
        • Zhong Z.
        • Darnell Jr., J.E.
        Cell. 1995; 82: 241-250
        • Giraud S.
        • Bienvenu F.
        • Avril S.
        • Gascan H.
        • Heery D.M.
        • Coqueret O.
        J. Biol. Chem. 2002; 277: 8004-8011
        • Giraud S.
        • Hurlstone A.
        • Avril S.
        • Coqueret O.
        Oncogene. 2004; 23: 7391-7398
        • Paulson M.
        • Pisharody S.
        • Pan L.
        • Guadagno S.
        • Mui A.L.
        • Levy D.E.
        J. Biol. Chem. 1999; 274: 25343-25349
        • Nakashima K.
        • Yanagisawa M.
        • Arakawa H.
        • Kimura N.
        • Hisatsune T.
        • Kawabata M.
        • Miyazono K.
        • Taga T.
        Science. 1999; 284: 479-482
        • Qin H.R.
        • Kim H.J.
        • Kim J.Y.
        • Hurt E.M.
        • Klarmann G.J.
        • Kawasaki B.T.
        • Duhagon Serrat M.A.
        • Farrar W.L.
        Cancer Res. 2008; 68: 7736-7741
        • Yang J.
        • Chatterjee-Kishore M.
        • Staugaitis S.M.
        • Nguyen H.
        • Schlessinger K.
        • Levy D.E.
        • Stark G.R.
        Cancer Res. 2005; 65: 939-947
        • Yang J.
        • Liao X.
        • Agarwal M.K.
        • Barnes L.
        • Auron P.E.
        • Stark G.R.
        Genes Dev. 2007; 21: 1396-1408
        • Lee H.
        • Herrmann A.
        • Deng J.H.
        • Kujawski M.
        • Niu G.
        • Li Z.
        • Forman S.
        • Jove R.
        • Pardoll D.M.
        • Yu H.
        Cancer Cell. 2009; 15: 283-293
        • Barré B.
        • Vigneron A.
        • Perkins N.
        • Roninson I.B.
        • Gamelin E.
        • Coqueret O.
        Trends Mol. Med. 2007; 13: 4-11
        • Sano S.
        • Chan K.S.
        • Kira M.
        • Kataoka K.
        • Takagi S.
        • Tarutani M.
        • Itami S.
        • Kiguchi K.
        • Yokoi M.
        • Sugasawa K.
        • Mori T.
        • Hanaoka F.
        • Takeda J.
        • DiGiovanni J.
        Cancer Res. 2005; 65: 5720-5729
        • Shen Y.
        • Devgan G.
        • Darnell Jr., J.E.
        • Bromberg J.F.
        Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 1543-1548
        • Niu G.
        • Wright K.L.
        • Ma Y.
        • Wright G.M.
        • Huang M.
        • Irby R.
        • Briggs J.
        • Karras J.
        • Cress W.D.
        • Pardoll D.
        • Jove R.
        • Chen J.
        • Yu H.
        Mol. Cell. Biol. 2005; 25: 7432-7440
        • Catlett-Falcone R.
        • Landowski T.H.
        • Oshiro M.M.
        • Turkson J.
        • Levitzki A.
        • Savino R.
        • Ciliberto G.
        • Moscinski L.
        • Fernández-Luna J.L.
        • Nuñez G.
        • Dalton W.S.
        • Jove R.
        Immunity. 1999; 10: 105-115
        • Duan Z.
        • Foster R.
        • Bell D.A.
        • Mahoney J.
        • Wolak K.
        • Vaidya A.
        • Hampel C.
        • Lee H.
        • Seiden M.V.
        Clin. Cancer Res. 2006; 12: 5055-5063
        • Diaz N.
        • Minton S.
        • Cox C.
        • Bowman T.
        • Gritsko T.
        • Garcia R.
        • Eweis I.
        • Wloch M.
        • Livingston S.
        • Seijo E.
        • Cantor A.
        • Lee J.H.
        • Beam C.A.
        • Sullivan D.
        • Jove R.
        • Muro-Cacho C.A.
        Clin. Cancer Res. 2006; 12: 20-28
        • Gritsko T.
        • Williams A.
        • Turkson J.
        • Kaneko S.
        • Bowman T.
        • Huang M.
        • Nam S.
        • Eweis I.
        • Diaz N.
        • Sullivan D.
        • Yoder S.
        • Enkemann S.
        • Eschrich S.
        • Lee J.H.
        • Beam C.A.
        • Cheng J.
        • Minton S.
        • Muro-Cacho C.A.
        • Jove R.
        Clin. Cancer Res. 2006; 12: 11-19
        • Vigneron A.
        • Roninson I.B.
        • Gamelin E.
        • Coqueret O.
        Cancer Res. 2005; 65: 8927-8935
        • Vigneron A.
        • Gamelin E.
        • Coqueret O.
        Cancer Res. 2008; 68: 815-825
        • Dhavan R.
        • Tsai L.H.
        Nat. Rev. Mol. Cell Biol. 2001; 2: 749-759
        • Gong X.
        • Tang X.
        • Wiedmann M.
        • Wang X.
        • Peng J.
        • Zheng D.
        • Blair L.A.
        • Marshall J.
        • Mao Z.
        Neuron. 2003; 38: 33-46
        • Wang C.X.
        • Song J.H.
        • Song D.K.
        • Yong V.W.
        • Shuaib A.
        • Hao C.
        Cell Death Differ. 2006; 13: 1203-1212
        • Vigneron A.
        • Cherier J.
        • Barré B.
        • Gamelin E.
        • Coqueret O.
        J. Biol. Chem. 2006; 281: 34742-34750
        • Le H.V.
        • Minn A.J.
        • Massagué J.
        J. Biol. Chem. 2005; 280: 32018-32025
        • Turner N.C.
        • Lord C.J.
        • Iorns E.
        • Brough R.
        • Swift S.
        • Elliott R.
        • Rayter S.
        • Tutt A.N.
        • Ashworth A.
        EMBO J. 2008; 27: 1368-1377
        • Tian B.
        • Yang Q.
        • Mao Z.
        Nat. Cell Biol. 2009; 11: 211-218
        • Alexander K.
        • Yang H.S.
        • Hinds P.W.
        Mol. Cell. Biol. 2004; 24: 2808-2819
        • Yang H.S.
        • Hinds P.W.
        Mol. Cell. 2003; 11: 1163-1176
        • Fu A.K.
        • Fu W.Y.
        • Ng A.K.
        • Chien W.W.
        • Ng Y.P.
        • Wang J.H.
        • Ip N.Y.
        Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 6728-6733
        • Lee J.H.
        • Jeong M.W.
        • Kim W.
        • Choi Y.H.
        • Kim K.T.
        J. Biol. Chem. 2008; 283: 19826-19835
        • Leslie K.
        • Lang C.
        • Devgan G.
        • Azare J.
        • Berishaj M.
        • Gerald W.
        • Kim Y.B.
        • Paz K.
        • Darnell J.E.
        • Albanese C.
        • Sakamaki T.
        • Pestell R.
        • Bromberg J.
        Cancer Res. 2006; 66: 2544-2552
        • Lo H.W.
        • Hsu S.C.
        • Ali-Seyed M.
        • Gunduz M.
        • Xia W.
        • Wei Y.
        • Bartholomeusz G.
        • Shih J.Y.
        • Hung M.C.
        Cancer Cell. 2005; 7: 575-589
        • Kiuchi N.
        • Nakajima K.
        • Ichiba M.
        • Fukada T.
        • Narimatsu M.
        • Mizuno K.
        • Hibi M.
        • Hirano T.
        J. Exp. Med. 1999; 189: 63-73
        • Bowman T.
        • Broome M.A.
        • Sinibaldi D.
        • Wharton W.
        • Pledger W.J.
        • Sedivy J.M.
        • Irby R.
        • Yeatman T.
        • Courtneidge S.A.
        • Jove R.
        Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 7319-7324
        • Barré B.
        • Avril S.
        • Coqueret O.
        J. Biol. Chem. 2003; 278: 2990-2996
        • Barré B.
        • Vigneron A.
        • Coqueret O.
        J. Biol. Chem. 2005; 280: 15673-15681
        • Dendouga N.
        • Gao H.
        • Moechars D.
        • Janicot M.
        • Vialard J.
        • McGowan C.H.
        Mol. Cell. Biol. 2005; 25: 7569-7579
        • Osman F.
        • Whitby M.C.
        DNA Repair. 2007; 6: 1004-1017
        • Pommier Y.
        • Redon C.
        • Rao V.A.
        • Seiler J.A.
        • Sordet O.
        • Takemura H.
        • Antony S.
        • Meng L.
        • Liao Z.
        • Kohlhagen G.
        • Zhang H.
        • Kohn K.W.
        Mutat. Res. 2003; 532: 173-203
        • Chatterjee-Kishore M.
        • Wright K.L.
        • Ting J.P.
        • Stark G.R.
        EMBO J. 2000; 19: 4111-4122
        • Townsend P.A.
        • Cragg M.S.
        • Davidson S.M.
        • McCormick J.
        • Barry S.
        • Lawrence K.M.
        • Knight R.A.
        • Hubank M.
        • Chen P.L.
        • Latchman D.S.
        • Stephanou A.
        J. Cell Sci. 2005; 118: 1629-1639
        • Thomas M.
        • Finnegan C.E.
        • Rogers K.M.
        • Purcell J.W.
        • Trimble A.
        • Johnston P.G.
        • Boland M.P.
        Cancer Res. 2004; 64: 8357-8364
        • Slupianek A.
        • Schmutte C.
        • Tombline G.
        • Nieborowska-Skorska M.
        • Hoser G.
        • Nowicki M.O.
        • Pierce A.J.
        • Fishel R.
        • Skorski T.
        Mol. Cell. 2001; 8: 795-806
        • Slupianek A.
        • Hoser G.
        • Majsterek I.
        • Bronisz A.
        • Malecki M.
        • Blasiak J.
        • Fishel R.
        • Skorski T.
        Mol. Cell. Biol. 2002; 22: 4189-4201
        • Shields B.J.
        • Hauser C.
        • Bukczynska P.E.
        • Court N.W.
        • Tiganis T.
        Cancer Cell. 2008; 14: 166-179
        • Vafa O.
        • Wade M.
        • Kern S.
        • Beeche M.
        • Pandita T.K.
        • Hampton G.M.
        • Wahl G.M.
        Mol. Cell. 2002; 9: 1031-1044
        • Campbell K.J.
        • Witty J.M.
        • Rocha S.
        • Perkins N.D.
        Cancer Res. 2006; 66: 929-935
        • Lin H.
        • Chen M.C.
        • Chiu C.Y.
        • Song Y.M.
        • Lin S.Y.
        J. Biol. Chem. 2007; 282: 2776-2784
        • Flørenes V.A.
        • Lu C.
        • Bhattacharya N.
        • Rak J.
        • Sheehan C.
        • Slingerland J.M.
        • Kerbel R.S.
        Oncogene. 1999; 18: 1023-1032
        • Bienvenu F.
        • Barre B.
        • Giraud S.
        • Avril S.
        • Coqueret O.
        Mol. Biol. Cell. 2005; 16: 1850-1858
        • Johnstone R.W.
        • Ruefli A.A.
        • Lowe S.W.
        Cell. 2002; 108: 153-164
        • Henderson B.W.
        • Daroqui C.
        • Tracy E.
        • Vaughan L.A.
        • Loewen G.M.
        • Cooper M.T.
        • Baumann H.
        Clin. Cancer Res. 2007; 13: 3156-3163
        • Benekli M.
        • Baumann H.
        • Wetzler M.
        J. Clin. Oncol. 2009; 27: 4422-4432