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http://dx.doi.org/10.14348/molcells.2020.2231

DNAJB9 Inhibits p53-Dependent Oncogene-Induced Senescence and Induces Cell Transformation  

Lee, Hyeon Ju (Department of Biochemistry and Molecular Biology, Kangwon National University School of Medicine)
Jung, Yu-Jin (Department of Biological Sciences, Kangwon National University)
Lee, Seungkoo (Department of Anatomic Pathology, Kangwon National University School of Medicine, Kangwon National University Hospital)
Kim, Jong-Il (Genomic Medicine Institute, Medical Research Center, Seoul National University)
Han, Jeong A. (Department of Biochemistry and Molecular Biology, Kangwon National University School of Medicine)
Abstract
DNAJB9 is known to be a member of the molecular chaperone gene family, whose cellular function has not yet been fully characterized. Here, we investigated the cellular function of DNAJB9 under strong mitogenic signals. We found that DNAJB9 inhibits p53-dependent oncogene-induced senescence (OIS) and induces neoplastic transformation under oncogenic RAS activation in mouse primary fibroblasts. In addition, we observed that DNAJB9 interacts physically with p53 under oncogenic RAS activation and that the p53-interacting region of DNAJB9 is critical for the inhibition of p53-dependent OIS and induction of neoplastic transformation by DNAJB9. These results suggest that DNAJB9 induces cell transformation under strong mitogenic signals, which is attributable to the inhibition of p53-dependent OIS by physical interactions with p53. This study might contribute to our understanding of the cellular function of DNAJB9 and the molecular basis of cell transformation.
Keywords
DNAJB9; p53; RAS; senescence; transformation;
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1 Kim, S.R., Park, J.H., Lee, M.E., Park, J.S., Park, S.C., and Han, J.A. (2008). Selective COX-2 inhibitors modulate cellular senescence in human dermal fibroblasts in a catalytic activity-independent manner. Mech. Ageing Dev. 129, 706-713.   DOI
2 Kuk, M.U., Kim, J.W., Lee, Y.S., Cho, K.A., Park, J.T., and Park, S.C. (2019). Alleviation of senescence via ATM inhibition in accelerated aging models. Mol. Cells 42, 210-217.   DOI
3 Kurisu, J., Honma, A., Miyajima, H., Kondo, S., Okumura, M., and Imaizumi, K. (2003). MDG1/ERdj4, an ER-resident DnaJ family member, suppresses cell death induced by ER stress. Genes Cells 8, 189-202.   DOI
4 Lee, H.J., Kim, J.M., Kim, K.H., Heo, J.I., Kwak, S.J., and Han, J.A. (2015). Genotoxic stress/p53-induced DNAJB9 inhibits the pro-apoptotic function of p53. Cell Death Differ. 22, 86-95.   DOI
5 Nardella, C., Clohessy, J.G., Alimonti, A., and Pandolfi, P.P. (2011). Prosenescence therapy for cancer treatment. Nat. Rev. Cancer 11, 503-511.   DOI
6 Narita, M., Nunez, S., Heard, E., Narita, M., Lin, A.W., Hearn, S.A., Spector, D.L., Hannon, G.J., and Lowe, S.W. (2003). Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703-716.   DOI
7 Ory, D.S., Neugeboren, B.A., and Mulligan, R.C. (1996). A stable humanderived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. Proc. Natl. Acad. Sci. U. S. A. 93, 11400-11406.   DOI
8 Qiu, X.B., Shao, Y.M., Miao, S., and Wang, L. (2006). The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cell. Mol. Life Sci. 63, 2560-2570.   DOI
9 Sarkisian, C.J., Keister, B.A., Stairs, D.B., Boxer, R.B., Moody, S.E., and Chodosh, L.A. (2007). Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat. Cell Biol. 9, 493-505.   DOI
10 Bartkova, J., Horejsi, Z., Koed, K., Kramer, A., Tort, F., Zieger, K., Guldberg, P., Sehested, M., Nesland, J.M., Lukas, C., et al. (2005). DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864-870.   DOI
11 Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.V., Kolettas, E., Niforou, K., Zoumpourlis, V.C., et al. (2006). Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633-637.   DOI
12 Benanti, J.A. and Galloway, D.A. (2004). Normal human fibroblasts are resistant to RAS-induced senescence. Mol. Cell. Biol. 24, 2842-2852.   DOI
13 Campisi, J. and d'Adda di Fagagna, F. (2007). Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729-740.   DOI
14 Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre, M., Nuciforo, P.G., Bensimon, A., et al. (2006). Oncogeneinduced senescence is a DNA damage response triggered by DNA hyperreplication. Nature 444, 638-642.   DOI
15 Cerami, E., Gao, J., Dogrusoz, U., Gross, B.E., Sumer, S.O., Aksoy, B.A., Jacobsen, A., Byrne, C.J., Heuer, M.L., Larsson, E., et al. (2012). The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401-404.   DOI
16 Choi, E.M., Kim, S.R., Lee, E.J., and Han, J.A. (2009). Cyclooxygenase-2 functionally inactivates p53 through a physical interaction with p53. Biochim. Biophys. Acta 1793, 1354-1365.   DOI
17 Courtois-Cox, S., Jones, S.L., and Cichowski, K. (2008). Many roads lead to oncogene-induced senescence. Oncogene 27, 2801-2809.   DOI
18 Di Micco, R., Fumagalli, M., and d'Adda di Fagagna, F. (2007). Breaking news: high-speed race ends in arrest--how oncogenes induce senescence. Trends Cell Biol. 17, 529-536.   DOI
19 Akagi, T. (2004). Oncogenic transformation of human cells: shortcomings of rodent model systems. Trends Mol. Med. 10, 542-548.   DOI
20 Ahn, B.Y., Trinh, D.L., Zajchowski, L.D., Lee, B., Elwi, A.N., and Kim, S.W. (2010). Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer. Oncogene 29, 1155-1166.   DOI
21 Awe, K., Lambert, C., and Prange, R. (2008). Mammalian BiP controls posttranslational ER translocation of the hepatitis B virus large envelope protein. FEBS lett. 582, 3179-3184.   DOI
22 Trinh, D.L., Elwi, A.N., and Kim, S.W. (2010). Direct interaction between p53 and Tid1 proteins affects p53 mitochondrial localization and apoptosis. Oncotarget 1, 396-404.   DOI
23 Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D., and Lowe, S.W. (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602.   DOI
24 Shen, Y., Meunier, L., and Hendershot, L.M. (2002). Identification and characterization of a novel endoplasmic reticulum (ER) DnaJ homologue, which stimulates ATPase activity of BiP in vitro and is induced by ER stress. J. Biol. Chem. 277, 15947-15956.   DOI
25 Tomayko, M.M. and Reynolds, C.P. (1989). Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother. Pharmacol. 24, 148-154.   DOI
26 Vos, M.J., Hageman, J., Carra, S., and Kampinga, H.H. (2008). Structural and functional diversities between members of the human HSPB, HSPH, HSPA, and DNAJ chaperone families. Biochemistry 47, 7001-7011.   DOI
27 Walsh, P., Bursac, D., Law, Y.C., Cyr, D., and Lithgow, T. (2004). The J-protein family: modulating protein assembly, disassembly and translocation. EMBO Rep. 5, 567-571.   DOI
28 Zhao, J.J., Roberts, T.M., and Hahn, W.C. (2004). Functional genetics and experimental models of human cancer. Trends Mol. Med. 10, 344-350.   DOI
29 Ferbeyre, G., de Stanchina, E., Lin, A.W., Querido, E., McCurrach, M.E., Hannon, G.J., and Lowe, S.W. (2002). Oncogenic ras and p53 cooperate to induce cellular senescence. Mol. Cell. Biol. 22, 3497-3508.   DOI
30 Dimri, G.P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E.E., Linskens, M., Rubelj, I., Pereira-Smith, O., et al. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U. S. A. 92, 9363-9367.   DOI
31 Gao, J., Aksoy, B.A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S.O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., et al. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1.
32 Halazonetis, T.D., Gorgoulis, V.G., and Bartek, J. (2008). An oncogeneinduced DNA damage model for cancer development. Science 319, 1352-1355.   DOI
33 Hanahan, D. and Weinberg, R.A. (2000). The hallmarks of cancer. Cell 100, 57-70.   DOI
34 Kang, T.W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011). Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547-551.   DOI
35 Hanahan, D. and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646-674.   DOI
36 Hartl, F.U., Bracher, A., and Hayer-Hartl, M. (2011). Molecular chaperones in protein folding and proteostasis. Nature 475, 324-332.   DOI
37 Jozefczuk, J., Drews, K., and Adjaye, J. (2012). Preparation of mouse embryonic fibroblast cells suitable for culturing human embryonic and induced pluripotent stem cells. J. Vis. Exp. 64, 3854.