MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop

Science Signaling

Volumn 4, Issue 160, 2011, Pages

  Ahmad, Rehan ^a   Rajabi, Hasan ^a   Kosugi, Michio ^a   Joshi, Maya Datt ^a   Alam, Maroof ^a   Vasir, Baldev ^a   Kawano, Takeshi ^a,b   Kharbanda, Surender ^a,c   Kufe, Donald ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

^b JIKEI UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^c Department of Genus Oncology   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; GO 201; INTERLEUKIN 10; INTERLEUKIN 22; INTERLEUKIN 6; JANUS KINASE 1; MUCIN; MUCIN 1 CARBOXYL TERMINAL RECEPTOR SUBUNIT; ONCOPROTEIN; PROTEIN INHIBITOR; STAT3 PROTEIN; UNCLASSIFIED DRUG; HYBRID PROTEIN; JAK1 PROTEIN, HUMAN; LUCIFERASE; MUC1 PROTEIN, HUMAN; MUCIN 1; MULTIPROTEIN COMPLEX; PEPTIDE; PROTEIN SUBUNIT;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BREAST CANCER; BREAST EPITHELIUM; BREAST TUMOR; CANCER CELL; CELL SURVIVAL; CONFOCAL MICROSCOPY; CONTROLLED STUDY; DRUG INHIBITION; ENZYME ACTIVITY; FEMALE; GENE TARGETING; HUMAN; HUMAN CELL; IMMUNOFLUORESCENCE MICROSCOPY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN FUNCTION; PROTEIN INTERACTION; BINDING SITE; CELL LINE; CELL STRAIN HEK293; DRUG EFFECT; GENETICS; HOMEOSTASIS; IMMUNOBLOTTING; IMMUNOPRECIPITATION; METABOLISM; PHOSPHORYLATION; PROTEIN BINDING; RNA INTERFERENCE; TUMOR CELL LINE;

BINDING SITES; CELL LINE; CELL LINE, TUMOR; HEK293 CELLS; HOMEOSTASIS; HUMANS; IMMUNOBLOTTING; IMMUNOPRECIPITATION; INTERLEUKIN-6; JANUS KINASE 1; LUCIFERASES; MICROSCOPY, CONFOCAL; MUCIN-1; MULTIPROTEIN COMPLEXES; PEPTIDES; PHOSPHORYLATION; PROMOTER REGIONS, GENETIC; PROTEIN BINDING; PROTEIN SUBUNITS; RECOMBINANT FUSION PROTEINS; RNA INTERFERENCE; STAT3 TRANSCRIPTION FACTOR;

EID: 79951904086     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.2001426     Document Type: Article

References (51)

1. B. B. Aggarwal, A. B. Kunnumakkara, K. B. Harikumar, S. R. Gupta, S. T. Tharakan, C. Koca, S. Dey, B. Sung, Signal transducer and activator of transcription-3, inflammation, and cancer: How intimate is the relationship? Ann. N. Y. Acad. Sci. 1171, 59-76 (2009).
2. U. M. Wegenka, C. Lütticken, J. Buschmann, J. Yuan, F. Lottspeich, W. Müller-Esterl, C. Schindler, E. Roeb, P. C. Heinrich, F. Horn, The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family. Mol. Cell. Biol. 14, 3186-3196 (1994).
3. J. V. Alvarez, H. Greulich, W. R. Sellers, M. Meyerson, D. A. Frank, Signal transducer and activator of transcription 3 is required for the oncogenic effects of non - small-cell lung cancer - associated mutations of the epidermal growth factor receptor. Cancer Res. 66, 3162-3168 (2006).
4. J. V. Alvarez, P. G. Febbo, S. Ramaswamy, M. Loda, A. Richardson, D. A. Frank, Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors. Cancer Res. 65, 5054-5062 (2005).
5. J. F. Bromberg, M. H. Wrzeszczynska, G. Devgan, Y. Zhao, R. G. Pestell, C. Albanese, J. E. Darnell Jr., Stat3 as an oncogene. Cell 98, 295-303 (1999).
6. D. S. Aaronson, C. M. Horvath, A road map for those who don't know JAK-STAT. Science 296, 1653-1655 (2002).
7. T. Bowman, R. Garcia, J. Turkson, R. Jove, STATs in oncogenesis. Oncogene 19, 2474-2488 (2000).
8. H. Yu, R. Jove, The STATs of cancer - new molecular targets come of age. Nat. Rev. Cancer 4, 97-105 (2004).
9. J. Yang, M. Chatterjee-Kishore, S. M. Staugaitis, H. Nguyen, K. Schlessinger, D. E. Levy, G. R. Stark, Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res. 65, 939-947 (2005).
10. J. Yang, X. Liao, M. K. Agarwal, L. Barnes, P. E. Auron, G. R. Stark, Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB. Genes Dev. 21, 1396-1408 (2007).
11. M. Ichiba, K. Nakajima, Y. Yamanaka, N. Kiuchi, T. Hirano, Autoregulation of the Stat3 gene through cooperation with a cAMP-responsive element-binding protein. J. Biol. Chem. 273, 6132-6138 (1998).
12. H. Song, R. Wang, S. Wang, J. Lin, A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc. Natl. Acad. Sci. U.S.A. 102, 4700-4705 (2005).
13. K. Siddiquee, S. Zhang, W. C. Guida, M. A. Blaskovich, B. Greedy, H. R. Lawrence, M. L. Yip, R. Jove, M. M. McLaughlin, N. J. Lawrence, S. M. Sebti, J. Turkson, Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc. Natl. Acad. Sci. U.S.A. 104, 7391-7396 (2007).
14. R. Ahmad, D. Raina, C. Meyer, D. Kufe, Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)→signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3. Cancer Res. 68, 2920-2926 (2008).
15. D. Germain, D. A. Frank, Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin. Cancer Res. 13, 5665-5669 (2007).
16. C. Buerger, K. Nagel-Wolfrum, C. Kunz, I. Wittig, K. Butz, F. Hoppe-Seyler, B. Groner, Sequence-specific peptide aptamers, interacting with the intracellular domain of the epidermal growth factor receptor, interfere with Stat3 activation and inhibit the growth of tumor cells. J. Biol. Chem. 278, 37610-37621 (2003).
17. D. W. Kufe, Mucins in cancer: Function, prognosis and therapy. Nat. Rev. Cancer 9, 874-885 (2009).
18. Y. Li, D. Liu, D. Chen, S. Kharbanda, D. Kufe, Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 22, 6107-6110 (2003).
19. L. Huang, D. Chen, D. Liu, L. Yin, S. Kharbanda, D. Kufe, MUC1 oncoprotein blocks glycogen synthase kinase 3β-mediated phosphorylation and degradation of β-catenin. Cancer Res. 65, 10413-10422 (2005).
20. M. J. Ligtenberg, L. Kruijshaar, F. Buijs, M. van Meijer, S. V. Litvinov, J. Hilkens, Cell-associated episialin is a complex containing two proteins derived from a common precursor. J. Biol. Chem. 267, 6171-6177 (1992).
21. B. Macao, D. G. Johansson, G. C. Hansson, T. Härd, Autoproteolysis coupled to protein folding in the SEA domain of the membrane-bound MUC1 mucin. Nat. Struct. Mol. Biol. 13, 71-76 (2006).
22. S. Ramasamy, S. Duraisamy, S. Barbashov, T. Kawano, S. Kharbanda, D. Kufe, The MUC1 and galectin-3 oncoproteins function in a microRNA-dependent regulatory loop. Mol. Cell 27, 992-1004 (2007).
23. Y. Leng, C. Cao, J. Ren, L. Huang, D. Chen, M. Ito, D. Kufe, Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62. J. Biol. Chem. 282, 19321-19330 (2007).
24. R. Ahmad, D. Raina, V. Trivedi, J. Ren, H. Rajabi, S. Kharbanda, D. Kufe, MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signaling. Nat. Cell Biol. 9, 1419-1427 (2007).
25. R. Ahmad, D. Raina, M. D. Joshi, T. Kawano, J. Ren, S. Kharbanda, D. Kufe, MUC1-C oncoprotein functions as a direct activator of the nuclear factor-κB p65 transcription factor. Cancer Res. 69, 7013-7021 (2009).
26. X. Wei, H. Xu, D. Kufe, Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell 7, 167-178 (2005).
27. X. Wei, H. Xu, D. Kufe, MUC1 oncoprotein stabilizes and activates estrogen receptor α. Mol. Cell 21, 295-305 (2006).
28. J. Ren, N. Agata, D. Chen, Y. Li, W.-H. Yu, L. Huang, D. Raina, W. Chen, S. Kharbanda, D. Kufe, Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents. Cancer Cell 5, 163-175 (2004).
29. J. Ren, A. Bharti, D. Raina, W. Chen, R. Ahmad, D. Kufe, MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90. Oncogene 25, 20-31 (2006).
30. L. M. Neilson, J. Zhu, J. Xie, M. G. Malabarba, K. Sakamoto, K. U. Wagner, R. A. Kirken, H. Rui, Coactivation of janus tyrosine kinase (Jak)1 positively modulates prolactin- Jak2 signaling in breast cancer: Recruitment of ERK and signal transducer and activator of transcription (Stat)3 and enhancement of Akt and Stat5a/b pathways. Mol. Endocrinol. 21, 2218-2232 (2007).
31. P. C. Heinrich, I. Behrmann, G. Muller-Newen, F. Schaper, L. Graeve, Interleukin-6- type cytokine signalling through the gp130/Jak/STAT pathway.Biochem. J. 334, 297-314 (1998).
32. D. Lejeune, L. Dumoutier, S. Constantinescu, W. Kruijer, J. J. Schuringa, J. C. Renauld, Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J. Biol. Chem. 277, 33676-33682 (2002).
33. P. J. Murray, The JAK-STAT signaling pathway: Input and output integration. J. Immunol. 178, 2623-2629 (2007).
34. I. C. Gaemers, H. L. Vos, H. H. Volders, S. W. van der Valk, J. Hilkens, A STAT-responsive element in the promoter of the episialin/MUC1 gene is involved in its overexpression in carcinoma cells. J. Biol. Chem. 276, 6191-6199 (2001).
35. D.Raina,R.Ahmad,M.D. Joshi, L.Yin,Z.Wu,T.Kawano,B.Vasir,D.Avigan, S. Kharbanda, D. Kufe, Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. Cancer Res. 69, 5133-5141 (2009).
36. K. Leslie, C. Lang, G. Devgan, J. Azare, M. Berishaj, W. Gerald, Y. B. Kim, K. Paz, J. E. Darnell, C. Albanese, T. Sakamaki, R. Pestell, J. Bromberg, Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res. 66, 2544-2552 (2006).
37. M. Berishaj, S. P. Gao, S. Ahmed, K. Leslie, H. Al-Ahmadie, W. L. Gerald, W. Bornmann, J. F. Bromberg, Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer. Breast Cancer Res. 9, R32 (2007).
38. R. G. Collum, S. Brutsaert, G. Lee, C. Schindler, A Stat3-interacting protein (StIP1) regulates cytokine signal transduction. Proc. Natl. Acad. Sci. U.S.A. 97, 10120-10125 (2000).
39. K. Shuai, Modulation of STAT signaling by STAT-interacting proteins. Oncogene 19, 2638-2644 (2000).
40. X. Zhang, M. H. Wrzeszczynska, C. M. Horvath, J. E. Darnell Jr., Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation. Mol. Cell. Biol. 19, 7138-7146 (1999).
41. Z. Yu, B. C. Kone, The STAT3 DNA-binding domain mediates interaction with NF-κB p65 and inducible nitric oxide synthase transrepression in mesangial cells. J. Am. Soc. Nephrol. 15, 585-591 (2004).
42. H. Lee, A. Herrmann, J. H. Deng, M. Kujawski, G. Niu, Z. Li, S. Forman, R. Jove, D. M. Pardoll, H. Yu, Persistently activated Stat3 maintains constitutive NF-kB activity in tumors. Cancer Cell 15, 283-293 (2009).
43. N. Khodarev, R. Ahmad, H. Rajabi, S. Pitroda, T. Kufe, C. McClary, M. D. Joshi, D. MacDermed, R. Weichselbaum, D. Kufe, Cooperativity of the MUC1 oncoprotein and STAT1 pathway in poor prognosis human breast cancer. Oncogene 29, 920-929 (2010).
44. M. D. Joshi, R. Ahmad, L. Yin, D. Raina, H. Rajabi, G. Bubley, S. Kharbanda, D. Kufe, MUC1 oncoprotein is a druggable target in human prostate cancer cells. Mol. Cancer Ther. 8, 3056-3065 (2009).
45. I. Herskowitz, Functional inactivation of genes by dominant negative mutations. Nature 329, 219-222 (1987).
46. R. A. Veitia, Dominant negative factors in health and disease. J. Pathol. 218, 409-418 (2009).
47. H. Yu, D. Pardoll, R. Jove, STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer 9, 798-809 (2009).
48. Q. Wang, J. S. Carroll, M. Brown, Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol. Cell 19, 631-642 (2005).
49. L. Yin, Y. Li, J. Ren, H. Kuwahara, D. Kufe, Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress. J. Biol. Chem. 278, 35458-35464 (2003).
50. T. Kawano, M. Ito, D. Raina, Z. Wu, J. Rosenblatt, D. Avigan, R. Stone, D. Kufe, MUC1 oncoprotein regulates Bcr-Abl stability and pathogenesis in chronic myelogenous leukemia cells. Cancer Res. 67, 11576-11584 (2007).
51. Funding: Thisworkwas supported by grantsCA97098,CA42802, andCA100707 awarded by the National Cancer Institute. Author contributions: R.A., H.R., M.K., M.D.J., M.A., and T.K. performed research and analyzed the data. B.V. contributed clinical samples. S.K. provided vital new reagents. D.K. designed the research and wrote the paper. Competing interests: S.K. is an employee of Genus Oncology, a company that focuses on the development of MUC1 therapeutics. D.K. holds equity in Genus Oncology and is a consultant to the company. The other authors declare that they have no competing interest.