Expression of Proteasome Activator REGγ in Human Laryngeal Carcinoma and Associations with Tumor Suppressor Proteins

  • Li, Li-Ping (Department of Otorhinolaryngology and Translational Neuroscience Center, West China Hospital of Sichuan University) ;
  • Cheng, Wei-Bo (Department of Pathology, West China School of Public Health, Sichuan University) ;
  • Li, Hong (The Joint Research Center, West China Second University Hospital and University of Hong Kong) ;
  • Li, Wen (Department of Otorhinolaryngology and Translational Neuroscience Center, West China Hospital of Sichuan University) ;
  • Yang, Hui (Department of Otorhinolaryngology and Translational Neuroscience Center, West China Hospital of Sichuan University) ;
  • Wen, Ding-Hou (Department of Otorhinolaryngology and Translational Neuroscience Center, West China Hospital of Sichuan University) ;
  • Tang, Yue-Di (Department of Otorhinolaryngology and Translational Neuroscience Center, West China Hospital of Sichuan University)
  • Published : 2012.06.30


The functional significance of the proteasome activator $REG{\gamma}$ in the regulation of cell proliferation and apoptosis has been recognized. However, pathological contributions to tumor development remain to be elucidated. Both oncogenic proteins and tumor suppressors are targeted by $REG{\gamma}$ for proteasomal degradation. It has been proposed that the role of the $REG{\gamma}$ in the pathogenesis of cancer is cell- and context-specific. In this study, we aimed to explore the potential involvement of $REG{\gamma}$ in laryngeal carcinomas, comparing protein expression in tumor and adjacent tissues by immunohistochemical staining and Western blot analysis. We also characterized the correlation between the expression of $REG{\gamma}$ and the previously identified substrates p53 and p21. We showed that $REG{\gamma}$ was abnormally highly expressed in cancer tissues. Statistical analysis revealed that there was a positive relationship between the level of $REG{\gamma}$ and the expression of p53 and p21. Our study suggests that $REG{\gamma}$ overexpression can facilitate the growth of laryngeal cancer cells.


  1. Ahn K, Erlander M, Leturcq D, et al (1996). In vivo characterization of the proteasome regulator PA28. J Biol Chem, 271, 18237-42.
  2. Barton LF, Runnels HA, Schell TD, et al (2004). Immune defects in 28-kDa proteasome activator gamma-deficient mice. J Immunol, 172, 3948-54.
  3. Bianchi S, Paglierani M, Zampi G, et al (1993). Prognostic value of proliferating cell nuclear antigen in lymph node-negative breast cancer patients. Cancer, 72, 120-5.<120::AID-CNCR2820720123>3.0.CO;2-8
  4. Bosari S, Viale G, Roncalli M, et al (1995). p53 gene mutations, p53 protein accumulation and compartmentalization in colorectal adenocarcinoma. Am J Pathol, 147, 790-8.
  5. Chen X, Barton LF, Chi Y, et al (2007). Ubiquitin-independent degradation of cell-cycle inhibitors by the REGgamma proteasome. Mol Cell, 26, 843-52.
  6. Ciechanover A (1994). The ubiquitin-proteasome proteolytic pathway. Cell, 79, 13-21.
  7. Ciechanover A (1998). The ubiquitin-proteasome pathway: on protein death and cell life. EMBOJ, 17, 7151-60.
  8. Ciechanover A, Orian A, Schwartz AL (2000). Ubiquitinmediated proteolysis: biological regulation via destruction. Bioessays, 22, 442-51.<442::AID-BIES6>3.0.CO;2-Q
  9. El-Deiry WS, Harper JW, O'Connor PM, et al (1994). WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res, 54, 1169-74.
  10. Finlay CA, Hinds PW, Tan TH, et al (1988). Activating mutations for transformation by p53 produce a gene product that forms an HSC 70-p53 complex with an altered half-life. Mol Cell Biol, 8, 531-9.
  11. Harper JW, Adami GR, Wei N, et al (1993). The p21 cdkinteracting protein Cip1 is a potent inhibitor of G1cyclindependent kinases. Cell, 75, 805-16.
  12. Hochstrasser M (1995). Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr. Opin. Cell Biol, 7, 215-23.
  13. Jin YT, Kayser S, Kemp BL, et al (1998). The Prognostic Significance of the Biomarkers p21WAF1/CIP1, p53, and bcl-2 in Laryngeal Squamous Cell Carcinoma. Cancer, 82, 2159-65.<2159::AID-CNCR10>3.0.CO;2-T
  14. Lane DP (1992). Cancer: p53, guardian of the genome. Nature, 358, 15-6.
  15. Li X, Amazit L, Long W, et al (2007). Ubiquitin- and ATPindependent proteolytic turnover of p21 by the REGgammaproteasome pathway. Mol Cell, 26, 831-42.
  16. Li X, Lonard DM, Jung SY, et al (2006). The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGgamma proteasome. Cell, 124, 381-92.
  17. Luo H, Wong J, Wong B (2010). Protein degradation systems in viral myocarditis leading to dilated cardiomyopathy. Cardiovasc Res, 85, 347-56.
  18. Mao I, Liu J, Li X, et al (2008). REGgamma, a proteasome activator and beyond? Cell Mol Life Sci, 65, 3971-80.
  19. Murata S, Kawahara H, Tohma S, et al (1999). Growth retardation in mice lacking the proteasome activator PA28gamma. J Biol Chem, 274, 38211-5.
  20. Okamura T, Taniguchi S, Ohkura T, et al (2003). Abnormally high expression of proteasome activator-gamma in thyroid neoplasm. J Clin Endocrinol. Metab, 88, 1374-83.
  21. Powell J, Robin PE (1983). Cancer of the head and neck: the present state. In: Head and Neck Cancer. Rhys Evans P, Robin PE & Fielding JWL (eds). Castle House: Tunbridge Wells.
  22. Realini C, Jensen CC, Zhang Z, et al (1997). Characterization of recombinant REGalpha, REGbeta, and REGgamma proteasome activators. J Biol Chem, 272, 25483-92.
  23. Reich NC, Oven M, Levine AJ (1983). Two distinct mechanisms regulate the levels of cellular tumor antigen p53. Mol Cell Biol, 3, 2143-50.
  24. Roessler M, Rollinger W, Mantovani-Endl L, et al (2006). Identification of PSME3 as a novel serum tumor marker for colorectal cancer by combining two-dimensional polyacrylamide gel electrophoresis with a strictly mass spectrometry-based approach for data analysis. Mol Cell Proteomics, 5, 2092-101.
  25. Roninson IB (2002). Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts. Cancer Lett, 179, 1-14.
  26. Sarafoleanu D, Postelnicu V, Iosif C, et al (2009). The role of p53, PCNA and Ki-67 as outcome predictors in the treatment of laryngeal cancer. J Med Life, 2, 219-26.
  27. Sharpless NE and DePinho RA (2002). p53: good cop/bad cop. Cell, 110, 9-12.
  28. Shunqian J, Qimin Z (2002). Oncomolecularbiology is the forefront of basic medical research. World Chin J Dig, 10, 678-80.
  29. Soza A, Knuehl C, Groettrup M, et al (1997). Expression and subcellular localization of mouse 20S proteasome activator complex PA28. FEBS Lett, 413, 27-34.
  30. Tomohisa O, Shin-Ichi T, Tsuyoshi O, et al (2003). Abnormally high expression of proteasome activator-cin Thyroid neoplasm. J Clin Endocrinol Metab, 88, 1374-83.
  31. Wang XY, Tu SF, Tan JX, et al (2009). REG gamma: a potential marker in breast cancer and effect on cell cycle and proliferation of breast cancer cell. Med Oncol, 28, 31-41.
  32. Weinberg WC, Denning MF (2002). P21Waf1 control of epithelial cell cycle and cell fate. Crit Rev Oral Biol Med, 13, 453-64.
  33. Wojcik C, Tanaka K, Paweletz N, et al (1998). Proteasome activator (PA28) subunits, ${\alpha}$, ${\beta}$ and ${\gamma}$ (Ki antigen) in NT2 neuronal precursor cells and HeLa S3 cells. Eur J Cell Biol, 77, 151-60.
  34. Ying H, Furuya F, Zhao L, et al (2006). Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone beta receptor inhibits mitotic progression. J Clin Invest, 116, 2972-84.
  35. Zhang M, Gan L, Ren GS (2012). REG${\gamma}$ is a strong candidate for the regulation of cell cycle, proliferation and the invasion by poorly differentiated thyroid carcinoma cells. Braz J Med Biol Res, 45, 459-65.
  36. Zhang Z, Zhang R (2008). Proteasome activator PA28 gamma regulates p53 by enhancing its MDM2-mediated degradation. EMBO J, 27, 852-64.

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