Abstract
Overexpression of mac25 in the prostate cancer cell line M12 effects a dramatic reversal of the transformed phenotype. cDNA array analysis of RNA from cells overproducing the mac25 protein (M12/mac25) indicated upregulation of the sex determining transcription factor SOX9. In this study, we have confirmed increased expression of SOX9 in M12/mac25 cells and have further investigated the physiological effects of increased SOX9 production. Greatly increased levels of SOX9 RNA and mature protein were demonstrated in cells transfected with a SOX9 cDNA (M12/SOX9), and gel mobility shift assays confirmed binding of nuclear protein from these cells to an oligonucleotide containing the SOX9 consensus binding sequence. M12/SOX9 cells assumed the spindle-shaped morphology characteristic of M12/mac25 cells, suggesting that SOX9 mediates some effects of mac25. Elevated expression of SOX9 resulted in a decreased rate of cellular proliferation, cell cycle arrest in G0/G1, and increased sensitivity to apoptosis. Tumor development in athymic nude mice was inhibited by 80%. Finally, prostate-specific antigen and the androgen receptor, two genes whose expression is characteristic of differentiated cells, were both upregulated in M12/SOX9 cells. These data indicate that SOX9 contributes to growth regulation by mac25 via inhibition of cell growth and promotion of differentiation.
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References
Afonja O, Raaka BM, Huang A, Das S, Zhao X, Helmer E, Juste D and Samuels HH . (2002). Oncogene, 21, 7850–7860.
Bae VL, Jackson-Cook CK, Maygarden SJ, Plymate SR, Chen J and Ware JL . (1998). Prostate, 34, 275–282.
Bowles J and Koopman P . (2001). Genome Biol., 2, 10251–10254.
Burger A, Zhang X, Li H, Ostrowski J, Beatty B, Venanzoni M, Papas T and Seth A . (1997). Oncogene, 16, 2459–2467.
Chomczysnki P and Sacchi N . (1987). Anal. Biochem., 162, 156–159.
Clarkson MJ and Harley VR . (2002). Trends Endocrinol. Metab., 13, 106–111.
Damon SE, Maddison L, Ware JL and Plymate SR . (1998). Endocrinology, 139, 3456–3464.
Drivdahl RH, Sprenger CC, Trimm K and Plymate SR . (2001). Endocrinology, 142, 1990–1998.
Feinberg AP and Vogelstein B . (1983). Anal. Biochem., 132, 6–13.
Fourney RM, Day RS and Paterson MC . (1989). Focus, 10, 5–7.
Graff JR, Konicek BW, McNulty MN, Wang Z, Houck K, Allen S, Paul JD, Hbaiu A, Goode RG, Sandusky GF, Vessella RL and Neubauer BL . (2000). J. Biol. Chem., 275, 24500–24505.
Graves JA . (1998). BioEssays, 20, 264–269.
Healy C, Uwanogho D and Sharpe PT . (1999). Dev. Dyn., 215, 69–78.
Hossenlopp P, Seurin D, Segovia-Quinson B, Hardouin S and Binoux M . (1986). Anal. Biochem., 154, 138–143.
Hwa V, Tomasini-Sprenger C, Bermejo AB, Rosenfeld RG and Plymate SR . (1998). J. Clin. Endocinol., 83, 4355–4362.
Kanai Y and Koopman P . (1999). Hum. Mol. Genet., 8, 691–696.
Kato M, Sato H, Tsukada T, Ikawa Y, Aizawa S and Nagayoshi MA . (1996). Oncogene, 12, 1361–1364.
Kent J, Wheatley SC, Andrews JE, Sinclair AH and Koopman P . (1996). Development, 122, 2813–2822.
Kishibe J, Yamada S, Okada Y, Sato J, Ito A, Miyazaki K and Sugahara K . (2000). J. Biol. Chem., 275, 15321–15329.
Komatsu K, Okazaki Y, Tateno M, Kawai J, Konno H, Kusakabe K, Yoshiki A, Muramatsu M, Held WA and Hayashizaki Y . (2001). Biochem. Biophys. Res. Commun., 276, 109–117.
Koopman P, Bullejos M and Bowles J . (2001). J. Exp. Zool., 290, 463–474.
Lefebvre V, Huang W, Harley VR, Goodfellow PN and deCrombrugghe B . (1997). Mol. Cell. Biol., 17, 2336–2346.
Lehrach H, Diamond D, Wozney JM and Boedtker H . (1977). Biochemistry, 16, 4743–4749.
Li N, Oberley TD, Oberley LW and Zhong W . (1998). J. Cell. Physiol., 175, 359–369.
Lin HK, Yeh, Kang HY and Chang C . (2001). Proc. Natl. Acad. Sci. USA, 98, 7200–7205.
Lopez-Bermejo A, Buckway CK, Devi GR, Hwa V, Plymate SR, Oh Y and Rosenfeld RG . (2000). Endocrinology, 141, 4072–4080.
Lu S, Jenster G and Epner DE . (2000). Mol. Endocrinol., 14, 753–760.
Marshall OJ and Harley VR . (2000). Mol. Genet. Metab., 71, 455–462.
Miller GJ . (1999). Cancer Metastasis Rev., 17, 353–360.
Murakami S, Kan M, McKeehan WL and deCrombrugghe B . (2000). Proc. Natl. Acad. Sci. USA, 97, 1113–1118.
Murillo H, Huang H, Schmidt L, Smith DI and Tindall DJ . (2001). Endocrinology, 142, 4795–4805.
Murphy M, Pykett M, Harnish P, Zang K and George D . (1993). Cell Growth Differ., 4, 715–722.
Oberley LW . (2001). Antioxidants Redox Signal., 3, 461–472.
Oh Y, Nagalla S, Yamanaka Y, Kim H, Wilson E and Rosenfeld R . (1996). J. Biol. Chem., 271, 30322–30325.
Olney PN, Kean LS, Graham D, Elsas LJ and May KM . (1999). Am. J. Med. Genet., 84, 20–24.
Panda D, Miao D, Lefebvre V, Hendy G and Goltzman D . (2001). J. Biol. Chem., 276, 41229–41236.
Peehl DM and Stamey TA . (1986). In vitro Cell Dev., 22, 82–90.
Plymate SR, Haugk KH, Sprenger CC, Nelson PS, Tennant MK, Zhang Y, Oberley LW, Zhong W, Drivdahl RH and Oberley TD . (2003). Oncogene, 22, 1024–1034.
Preiss S, Argentaro A, Clayton A, John A, Jans D, Ogata T, Nagai T, Barroso I, Schafer A and Harley VR . (2001). J. Biol. Chem., 276, 27864–27872.
Reinikaninen P, Palvimo JJ and Janne OA . (1996). Endocrinology, 137, 4351–4357.
Rhee SG, Bae Y, Lee SR and Kwon J . (2000). Science Sign. Trans. Knowl. Environ., 53, 1–6.
Rosenthal DS, Ding R, Simbulan-Rosenthal CM, Vaillancourt JP, Nicholson DW and Smulson M . (1997). Exp. Cell Res., 232, 313–321.
Sambrook J, Fritsch EF and Maniatis T . (1989). Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory: Cold Spring Harbor, NY.
Simbulan-Rosenthal CM, Rosenthal D, Luo R and Smulson M . (1999). Mol. Cell. Biochem., 193, 137–148.
Spokony RF, Aoki Y, Saint-Germain N, Magner-Fink E and Saint-Jeannet JP . (2002). Development, 129, 421–432.
Sprenger CC, Damon SE, Hwa V, Rosenfeld RG and Plymate SR . (1999). Cancer Res., 59, 2370–2375.
Sprenger CC, Vail ME, Evans K, Smurdak J and Plymate SR . (2002). Oncogene, 21, 140–147.
Swisshelm K, Ryan K, Tsuchiya K and Sager R . (1995). Proc. Natl. Acad. Sci. USA, 92, 4472–4476.
Tran CP, Lin C, Yamashiro J and Reiter RE . (2002). Mol. Cancer Res., 1, 113–121.
Ulrich A, Berman CH, Dull TJ, Gray A and Lee JM . (1984). EMBO J., 3, 361–364.
Vidal VP, Chaboissier MC, Rooij DG and Schedl A . (2001). Nat. Genet., 28, 216–217.
Vleminckx K and Kemmler R . (1999). BioEssays, 21, 211–220.
Wilson EM, Oh Y, Hwa V and Rosenfeld RG . (2001). J. Clin. Endocrinol. Metab., 86, 4504–4511.
Wilson HMP, Birnbaum R, Poot M, Quinn LS and Swisshelm K . (2002). Cell Growth Differ., 13, 205–213.
Yeh S, Lin HK, Kang HY, Thin TH, Lin MF and Chang C . (1999). Proc. Natl. Acad. Sci. USA, 96, 5458–5463.
Acknowledgements
This research was supported by PO1-CA85859 (to SRP and PSN), and RO1-56283 and Veterans Affairs Merit Review Program to SRP.
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Drivdahl, R., Haugk, K., Sprenger, C. et al. Suppression of growth and tumorigenicity in the prostate tumor cell line M12 by overexpression of the transcription factor SOX9. Oncogene 23, 4584–4593 (2004). https://doi.org/10.1038/sj.onc.1207603
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DOI: https://doi.org/10.1038/sj.onc.1207603
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