REGγ Mediated Regulation of p21<sup>Waf/Cip1</sup>, p16<sup>INK4a</sup> and p14<sup>ARF</sup>/p19<sup>ARF</sup> <i>in Vivo</i> — Oak Academic Publishing
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REGγ Mediated Regulation of p21<sup>Waf/Cip1</sup>, p16<sup>INK4a</sup> and p14<sup>ARF</sup>/p19<sup>ARF</sup> <i>in Vivo</i>
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
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Department of Pathology, The Second Chengdu Municipal Hospital, Chengdu, China
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The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
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The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
Department of Orthopaedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
,
The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
1 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
2 Department of Pathology, The Second Chengdu Municipal Hospital, Chengdu, China
3 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
4 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
5 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
6 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
7 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
8 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
9 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
10 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
11 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
12 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
13 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
14 Department of Orthopaedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai, China
15 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
16 The Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China
p 21 Waf/Cip1 , p16 INK4a and p14 ARF (p19 ARF in mice) have been demonstrated to be degraded by REG γ -proteasome pathway in an ATP- and ubiquitin-independent manner in vitro . However, the in vivo roles of REG γ mediated-degradation of p21 Waf/Cip1 , p16 INK4a and p14 ARF remain unclear. In this study, we showed enhanced expression of p21 Waf/Cip1 , p16 INK4a and p19 ARF in multiple tissues from REG g –/– mice compared to REG g +/+ mice. Furthermore, we examined the expression of p21 Waf/Cip1 , p16 INK4a and p14 ARF in different cancer tissues and observed that the REG γ protein levels were highly expressed in different human cancers while the level of p21 Waf/Cip1 , p16 INK4a and p14 ARF appears to be inversely corre lated. These results demonstrate that REG γ may exert its function in physiological and pathological conditions through degradation of p21 Waf/Cip1 , p16 INK4a and p14 ARF in vivo .
D. E. Quelle, F. Zindy, R. A. Ashmun, et al., “Alternative Reading Frames of the INK4a Tumor Suppressor Gene Encode Two Unrelated Proteins Capable of Inducing Cell Cycle Arrest,” Cell, Vol. 83, No. 6, 1995, pp. 993-1000. doi:10.1016/0092-8674(95)90214-7
S. W. Lowe and C. J. Sherr, “Tumor Suppression by INK4a-Arf: Progress and Puzzles,” Current Opinion in Genetics & Development, Vol. 13, No. 1, 2003, pp. 77-83. doi:10.1016/S0959-437X(02)00013-8
M. Serrano, H. Lee, L. Chin, et al., “Role of the INK4a Locus in Tumor Suppression and Cell Mortality,” Cell, Vol. 85, No. 1, 1996, pp. 27-37. doi:10.1016/S0092-8674(00)81079-X
P. Krimpenfort, K. C. Quon, W. J. Mooi, et al., “Loss of p16INK4a Confers Susceptibility to Metastatic Melanoma in Mice,” Nature, Vol. 413, No. 6851, 2001, pp. 83-86. doi:10.1038/35092584
M. Serrano, G. J. Hannon and D. Beach, “A New Regulatory Motif in Cell-Cycle Control Causing Specific Inhibition of Cyclin D/CDK4,” Nature, Vol. 366, No. 6456, 1993, pp. 704-707. doi:10.1038/366704a0
C. J. Sherr, “Principles of Tumor Suppression,” Cell, Vol. 116, No. 2, 2004, pp. 235-246. doi:10.1016/S0092-8674(03)01075-4
E. Sharpless and L. Chin, “The INK4a/ARF Locus and Melanoma,” Oncogene, Vol. 22, No. 20, 2003, pp. 3092-3098. doi:10.1038/sj.onc.1206461
R. Ben-Saadon, I. Fajerman, T. Ziv, et al., “The Tumor Suppressor Protein p16INK4a and the Human Papillomavirus Oncoprotein-58 E7 Are Naturally Occurring LysineLess Proteins That Are Degraded by the Ubiquitin System. Direct Evidence for Ubiquitination at the N-Terminal Residue,” The Journal of Biological Chemistry, Vol. 279, No. 40, 2004, pp. 41414-41421. doi:10.1074/jbc.M407201200
S. Bates, A. C. Phillips, P. A. Clark, et al., “p14ARF Links the Tumour Suppressors RB and p53,” Nature, Vol. 395, No. 6698, 1998, pp. 124-125. doi:10.1038/25867
I. Palmero, C. Pantoja and M. Serrano, “p19ARF Links the Tumour Suppressor p53 to Ras,” Nature, Vol. 395, No. 6698, 1998, pp. 125-126. doi:10.1038/25870
A. Radfar, I. Unnikrishnan, H. W. Lee, et al., “p19ARF Induces p53-Dependent Apoptosis during Abelson VirusMediated Pre-B Cell Transformation,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 22, 1998, pp. 13194-13199. doi:10.1073/pnas.95.22.13194
F. Zindy, R. T. Williams, T. A. Baudino, et al., “ARF Tumor Suppressor Promoter Monitors Latent Oncogenic Signals in Vivo,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 26, 2003, pp. 15930-15935. doi:10.1073/pnas.2536808100
R. Honda, and H. Yasuda, “Association of p19ARF with Mdm2 Inhibits Ubiquitin Ligase Activity of Mdm2 for Tumor Suppressor p53,” The EMBO Journal, Vol. 18, No. 1, 1999, pp. 22-27. doi:10.1093/emboj/18.1.22
C. A. Midgley, J. M. Desterro, M. K. Saville, et al., “An N-Terminal p14 ARF Peptide Blocks Mdm2-Dependent Ubiquitination in Vitro and Can Activate p53 in Vivo,” Oncogene, Vol. 19, No. 19, 2000, pp. 2312-2323.
X. Li, D. M. Lonard, S. Y. Jung, et al., “The SRC-3/AIB1 Coactivator Is Degraded in a Ubiquitinand ATP-Independent Manner by the REGγ Proteasome,” Cell, Vol. 124, No. 2, 2006, pp. 381-392. doi:10.1016/j.cell.2005.11.037
X. Chen, L. F. Barton, Y. Chi, et al., “Ubiquitin-Independent Degradation of Cell-Cycle Inhibitors by the REGγ Proteasome,” Molecular Cell, Vol. 26, No. 6, 2007, pp. 843-852. doi:10.1016/j.molcel.2007.05.022
X. Li, L. Amazit, W. Long, et al., “Ubiquitinand ATPIndependent Proteolytic Turnover of p21 by the REGgamma-Proteasome Pathway,” Molecular Cell, Vol. 26, No. 6, 2007, pp. 831-842. doi:10.1016/j.molcel.2007.05.028
T. Okamura, S. Taniguchi, T. Ohkura, et al., “Abnormally High Expression of Proteasome Activator-Gamma in Thyroid Neoplasm,” The Journal of Clinical Endocrinology & Metabolism, Vol. 88, No. 3, 2003, pp. 1374-1383.
M. Roessler, W. Rollinger, L. Mantovani-Endl, et al., “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,” Molecular & Cellular Proteomics, Vol. 5, No. 11, 2006, pp. 2092-2101. doi:10.1074/mcp.M600118-MCP200
Y. Hong, K. S. Ho, K. W. Eu, et al., “A Susceptibility Gene Set for Early Onset Colorectal Cancer That Integrates Diverse Signaling Pathways: Implication for Tumorigenesis,” Clinical Cancer Research, Vol. 13, No. 4, 2007, pp. 1107-1114. doi:10.1158/1078-0432.CCR-06-1633
H. L. Jia, Q. H. Ye, L. X. Qin, et al., “Gene Expression Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma,” Clinical Cancer Research, Vol. 13, No. 4, 2007, pp. 1133-1139. doi:10.1158/1078-0432.CCR-06-1025
J. He, L. Cui, Y. Zeng, et al., “REGγ Is Associated with Multiple Oncogenic Pathways in Human Cancers,” BMC Cancer, Vol. 12, 2012, p. 75. doi:10.1186/1471-2407-12-75
G. Yu, Y. Zhao, J. He, et al., “Comparative Analysis of REGγ Expression in Mouse and Human Tissues,” Journal of Molecular Cell Biology, Vol. 2, No. 4, 2010, pp. 192-198. doi:10.1093/jmcb/mjq009
G. Salvatore, T. C. Nappi, P. Salerno, et al., “A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma,” Cancer Research, Vol. 67, No. 21, 2007, pp. 10148-10158. doi:10.1158/0008-5472.CAN-07-1887
Y. Zhang, Y. Xiong and W. G. Yarbrough, “ARF Promotes MDM2 Degradation and Stabilizes p53: ARFINK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways,” Cell, Vol. 92, No. 6, 1998, pp. 725-734. doi:10.1016/S0092-8674(00)81401-4
L. F. Barton, H. A. Runnels, T. D. Schell, et al., “Immune Defects in 28-kDa Proteasome Activator Gamma-Deficient Mice,” The Journal of Immunology, Vol. 172, No. 6, 2004, pp. 3948-3954.
I. Mao, J. Liu, X. Li, et al., “REGγ, a Proteasome Activator and beyond?” Cellular and Molecular Life Sciences, Vol. 65, No. 24, 2008, pp. 3971-3980. doi:10.1007/s00018-008-8291-z
Z. Zhang and R. Zhang, “Proteasome Activator PA28 Gamma Regulates p53 by Enhancing Its MDM2-Mediated Degradation,” The EMBO Journal, Vol. 27, No. 6, 2008, pp. 852-864. doi:10.1038/emboj.2008.25