Abstract
Defects in interferon (IFN) signaling that result in loss of expression of IFN-inducible proteins are associated with cellular immortalization, an important early event in the development of human cancer. Here we report that loss of IFN-inducible IFI 16 expression in human fibroblasts allows bypass of cellular senescence. We found that levels of IFI 16 mRNA and protein were higher in human old versus young fibroblasts and immortalization of fibroblasts with telomerase resulted in decreased expression of IFI 16. Moreover, overexpression of IFI 16 in immortalized fibroblasts strongly inhibited cell proliferation. Interestingly, knockdown of IFI 16 expression in fibroblasts inhibited p53-mediated transcription, downregulated p21WAF1 expression, and extended the proliferation potential. Importantly, treatment of immortal cell lines with 5-aza-2′-deoxycytidine, an inhibitor of DNA methyltransferase, resulted in upregulation of IFI 16. Our observations support the idea that increased levels of IFI 16 in older populations of human fibroblasts contribute to cellular senescence.
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References
Aglipay JA, Lee SW, Okada S, Fujiuchi N, Ohtsuka T, Kwak JC, Wang Y, Johnstone RW, Deng C, Qin J and Ouchi T . (2003). Oncogene, 22, 8931–8938.
Akca H and Ozes ON . (2004). Scand. J. Clin. Lab. Invest., 63, 505–512.
Alani RM, Hasskarl J, Grace M, Hernandez MC, Israel MA and Munger K . (1999). Proc. Natl. Acad. Sci. USA, 96, 9637–9641.
Alani RM, Young AZ and Shifflett CB . (2001). Proc. Natl. Acad. Sci. USA, 98, 7812–7816.
Asefa B, Klarmann KD, Copeland NG, Gilbert DJ, Jenkins NA and Keller JR . (2004). Blood cells Mol. Dis., 32, 155–167.
Bertram MJ, Berube NG, Hang-Swanson X, Ran Q, Leung JK, Bryce S, Spurgers K, Bick RJ, Baldini A, Ning Y, Clark LJ, Parkinson EK, Barret JC, Smith JR and Pereira-Smith OM. . (1999). Mol. Cell. Biol., 19, 1479–1485.
Borden EC, Lindner D, Dreicer R, Hussein M and Peereboom D . (2000). Semin. Cancer Biol., 10, 125–144.
Brown JP, Wei W and Sedivy JM . (1997). Science, 277, 831–834.
Campisi J . (2001). Trends Cell Biol., 11, S27–S31.
Campisi J . (2003). Nat. Rev. Cancer, 3, 339–349.
Choubey D and Kotzin BL . (2002). Front. Biosci., 7, e252–e262.
Choubey D and Lengyel P . (1995). J. Biol. Chem., 270, 6134–6140.
Choubey D . (2000). J. Biol. Regul. Homeost. Agents, 14, 187–192.
Cong YS, Wright WE and Shay JW . (2002). Microbiol. Mol. Biol. Rev., 66, 407–425.
Dawson MJ and Trapani JA . (1995). Biochem. Biophys. Res. Commun., 214, 152–162.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I and Pereira-Smith O . (1995). Proc. Natl. Acad. Sci. USA, 92, 9363–9367.
Fujiuchi N, Aglipay JA, Ohtsuka T, Maehara N, Sahin F, Su GH, Lee SW and Ouchi T . (2004). J. Biol. Chem. Published online February 27.
Gutterman JU and Choubey D . (1999). Cell Growth Differ., 10, 93–100.
Hayflick L . (1965). Exp. Cell Res., 37, 614–636.
Hensler PJ, Annab LA, Barret JC and Pereira-Smith OM . (1994). Mol. Cell. Biol., 14, 2291–2297.
Johnstone RW and Trapani JA . (1999). Mol. Cell. Biol., 19, 5833–5838.
Johnstone RW, Wei W, Greenway A and Trapani JA . (2000). Oncogene, 19, 6033–6042.
Karlsson C, Stenman G, Vojta PJ, Bongcam-Rudoloff E, Barret JC, Westermark B and Paulsson Y . (1996). Cancer Res., 56, 241–245.
Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL and Shay JW . (1994). Science, 266, 2011–2015.
Kingsmore SF, Watson ML, Woward TA and Seldin MF . (1989). EMBO J., 8, 4073–4080.
Kulaeva OI, Draghici S, Tang L, Kraniak JM, Land SJ and Tainsky MA . (2003). Oncogene, 22, 4118–4127.
Kwak JC, Ongusaha PP, Ouchi T and Lee SW . (2003). J. Biol. Chem., 278, 40899–40904.
Lee SH, Kim JW, Lee HW, Cho YS, Oh SH, Kim YJ, Jung CH, Zhang W and Lee JH . (2003). Oncogene, 22, 381–391.
Lengyel, P, Choubey D, Li SJ and Datta B . (1995). Semin. Virol., 6, 203–213.
Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G and Hara E . (2001). Nature, 409, 1067–1070.
Raffaella R, Gioia D, De Andrea M, Cappello P, Giovarelli M, Marconi P, Manservigi R, Gariglio M and Landolfo S . (2004). Exp. Cell Res., 293, 331–345.
Sangfelt O, Erickson S, Castro J, Heiden T, Gustafsson A, Einhorn S and Grander D . (1999). Oncogene, 18, 2798–2810.
Sen GC and Lengyel P . (1992). J. Biol. Chem., 267, 5017–5020.
Sharpless NE and DePinho RA . (2002). Cell, 110, 9–12.
Shou J, Soriano R, Hayward SW, Cunha GR, Williams PM and Gao WQ . (2002). Proc. Natl. Acad. Sci. USA, 99, 2830–2835.
Sikder HA, Devlin MK, Dunlap S, Ryu B and Alani RM . (2003). Cancer Cell, 3, 525–530.
Smith JR and Pereira-Smith OM . (1996). Science, 273, 63–67.
Smith LL, Coller HA and Roberts JM . (2003). Nat. Cell Biol., 5, 474–479.
Stark GR, Kerr IM, Williams BR, Silverman RH and Schreiber RD . (1998). Annu. Rev. Biochem., 67, 227–264.
Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, Sasaki S, Imai K, Shibue T, Honda K and Taniguchi T . (2003). Nature, 424, 516–523.
Untergasser G, Koch HB, Menssen A and Hermeking H . (2002). Cancer Res., 62, 6255–6262.
Wang H, Chatterjee G, Meyer JJ, Liu CJ, Manjunath NA, Bray-Ward P and Lengyel P . (1999). Genomics, 60, 281–294.
Xin H, Curry J, Johnstone RW, Nickoloff BJ and Choubey D . (2003). Oncogene, 22, 4831–4840.
Young JI, Sedivy JM and Smith JR . (2003). J. Biol. Chem., 278, 19904–19908.
Acknowledgements
We thank Dr J Campisi for providing reagents and suggestions. We also thank Drs M Diaz, R Johnstone, and M Tainsky for discussions and suggestions. This work was supported by Grants AG022124 (to DC), PO1 AG20752 (to OMPS), and the Ellison Medical Foundation Award (to OMPS).
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Xin, H., Pereira-Smith, O. & Choubey, D. Role of IFI 16 in cellular senescence of human fibroblasts. Oncogene 23, 6209–6217 (2004). https://doi.org/10.1038/sj.onc.1207836
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DOI: https://doi.org/10.1038/sj.onc.1207836
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