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Pro-Apoptotic PUMA and Anti-Apoptotic Phospho-BAD Are Highly Expressed in Colorectal Carcinomas

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Abstract

Several lines of evidence indicate that, together with deregulated growth, alteration of apoptosis plays a pivotal role in tumorigenesis. PUMA, a pro-apoptotic member of Bcl-2 family, mediates p53-dependent and -independent apoptosis. BAD is also a pro-apoptotic Bcl-2 family member and phosphorylation of BAD protein inhibits the pro-apoptosis function of BAD. To see whether the alteration of protein expressions of PUMA and phospho-BAD (p-BAD) are characteristics of human colorectal cancers, we analyzed the expression of these proteins in 103 colorectal carcinomas by immunohistochemistry. Also, we analyzed the mutation of the Bcl-2 homology 3 (BH3) domain of PUMA gene, an important domain in the apoptosis function of PUMA, by single-strand conformation polymorphism (SSCP) in 98 colorectal carcinomas. p-BAD immunostaining was detected in 62 cases (60.1%) of the 103 carcinomas, whereas it was not detected in the normal colonic mucosal epithelial cells. PUMA protein expression was detected in both cancer cells and normal mucosal cells in all of the 103 cases. However, the cancer cells showed higher intensities of PUMA immunostaining than the normal cells of the same patients in 50.4% of the cases. There was no association of the p-BAD expression with the PUMA expression. The mutational analysis revealed no PUMA BH3 domain mutation in the cancers. Our data indicated that expressions of both PUMA and p-BAD were increased in the colorectal cancer cells, and suggested that the increased expression of these proteins in malignant colorectal epithelial cells compared to the normal mucosal epithelial cells may possibly alter the cell death regulation during colorectal tumorigenesis.

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References

  1. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

    Article  PubMed  CAS  Google Scholar 

  2. Reed JC (2000) Mechanisms of apoptosis. Am J Pathol 39:1415–1430

    Google Scholar 

  3. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  4. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291

    Article  PubMed  CAS  Google Scholar 

  5. Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B (2001) PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 7:673–682

    Article  PubMed  CAS  Google Scholar 

  6. Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB, Greenberg ME (2000) 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. Mol Cell 6:41–51

    Article  PubMed  CAS  Google Scholar 

  7. Hsu SY, Kaipia A, Zhu L, Hsueh AJ (1997) Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11. Mol Endocrinol 11:1858–1867

    Article  PubMed  CAS  Google Scholar 

  8. Tan Y, Demeter MR, Ruan H, Comb MJ (2000) BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival. J Biol Chem 275:25865–25869

    Article  PubMed  CAS  Google Scholar 

  9. Jeffers JR, Parganas E, Lee Y, Yang C, Wang J, Brennan J, MacLean KH, Han J, Chittenden T, Ihle JN, McKinnon PJ, Cleveland JL, Zambetti GP (2003) Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4:321–328

    Article  PubMed  CAS  Google Scholar 

  10. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, Korsmeyer SJ (1989) bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57:79–88

    Article  PubMed  CAS  Google Scholar 

  11. Lee JH, Soung YH, Lee JW, Park WS, Kim SY, Cho YG, Kim CJ, Seo SH, Kim HS, Nam SW, Yoo NJ, Lee SH, Lee JY (2004) Inactivating mutation of the pro-apoptotic gene BID in gastric cancer. J Pathol 202:439–445

    Article  PubMed  CAS  Google Scholar 

  12. Lee JW, Soung YH, Kim SY, Nam SW, Kim CJ, Cho YG, Lee JH, Kim HS, Park WS, Kim SH, Lee JY, Yoo NJ, Lee SH (2004) Inactivating mutations of proapoptotic Bad gene in human colon cancers. Carcinogenesis 25:1371–1376

    Article  PubMed  Google Scholar 

  13. Arena V, Martini M, Luongo M, Capelli A, Larocca LM (2003) Mutations of the BIK gene in human peripheral B-cell lymphomas. Genes Chromosomes Cancer 38:91–96

    Article  PubMed  CAS  Google Scholar 

  14. Kondo S, Shinomura Y, Miyazaki Y, Kiyohara T, Tsutsui S, Kitamura S, Nagasawa Y, Nakahara M, Kanayama S, Matsuzawa Y (2000) Mutations of the bak gene in human gastric and colorectal cancers. Cancer Res 60:4328–4330

    PubMed  CAS  Google Scholar 

  15. Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, Perucho M (1997) Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275:967–969

    Article  PubMed  CAS  Google Scholar 

  16. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847

    Article  PubMed  CAS  Google Scholar 

  17. Lee JY, Dong SM, Kim SY, Yoo NJ, Lee SH, Park WS (1998) A simple, precise and economical microdissection technique for analysis of genomic DNA from archival tissue sections. Virchows Arch 433:305–309

    Article  PubMed  CAS  Google Scholar 

  18. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628

    Article  PubMed  CAS  Google Scholar 

  19. Dramsi S, Scheid MP, Maiti A, Hojabrpour P, Chen X, Schubert K, Goodlett DR, Aebersold R, Duronio V (2002) Identification of a novel phosphorylation site, Ser-170, as a regulator of bad pro-apoptotic activity. J Biol Chem 277:6399–6405

    Article  PubMed  CAS  Google Scholar 

  20. Taghiyev AF, Guseva NV, Harada H, Knudson CM, Rokhlin OW, Cohen MB (2003) Overexpression of BAD potentiates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand treatment in the prostatic carcinoma cell line LNCaP. Mol Cancer Res 1:500–507

    PubMed  CAS  Google Scholar 

  21. Soung YH, Lee JW, Kim SY, Park WS, Nam SW, Lee JY, Yoo NJ, Lee SH (2004) Somatic mutations of CASP3 gene in human cancers. Hum Genet 115:112–115

    Article  PubMed  CAS  Google Scholar 

  22. Soung YH, Lee JW, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Park YG, Nam SW, Jeong SW, Kim SH, Lee JY, Yoo NJ, Lee SH (2003) Inactivating mutations of CASPASE-7 gene in human cancers. Oncogene 22:8048–8052

    Article  PubMed  Google Scholar 

  23. Kim HS, Lee JW, Soung YH, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Jeong SW, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH (2003) Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology 125:708–715

    Article  PubMed  CAS  Google Scholar 

  24. Hoque MO, Begum S, Sommer M, Lee T, Trink B, Ratovitski E, Sidransky D (2003) PUMA in head and neck cancer. Cancer Lett 199:75–81

    Article  PubMed  Google Scholar 

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Acknowledgment

This work was supported by funds from KOSEF (R01-2004-000-10463-0).

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Authors and Affiliations

  1. Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea

    Eun G Jeong, Jong W Lee, Young H Soung, Suk W Nam, Jung Y Lee, Nam J Yoo & Sug H Lee

  2. Department of Obstetrics/Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea

    Mi R Kim & Boa Chae

  3. Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul, 137-701, Korea

    Sug H Lee

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  1. Mi R Kim
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  2. Eun G Jeong
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  3. Boa Chae
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  4. Jong W Lee
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  5. Young H Soung
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  6. Suk W Nam
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  7. Jung Y Lee
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  8. Nam J Yoo
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  9. Sug H Lee
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Correspondence to Sug H Lee.

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Kim, M.R., Jeong, E.G., Chae, B. et al. Pro-Apoptotic PUMA and Anti-Apoptotic Phospho-BAD Are Highly Expressed in Colorectal Carcinomas. Dig Dis Sci 52, 2751–2756 (2007). https://doi.org/10.1007/s10620-007-9799-z

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  • DOI: https://doi.org/10.1007/s10620-007-9799-z

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