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TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

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Abstract

Increasing evidence suggests that tissue inhibitor of metalloproteinases-1 (TIMP-1) can directly regulate cell growth and apoptosis independent of its matrix metalloproteinases (MMPs)-inhibitory activity. While TIMP-1's antiapoptotic activity has been well demonstrated, conflicting data has been reported regarding TIMP-1's role in growth regulation. Here we show that TIMP-1 reduces the growth rate of human breast epithelial (MCF10A) cells by inducing cell cycle arrest at G1. TIMP-1-mediated cell cycle arrest is associated with its downregulation of cyclin D1 and upregulation of p27KIP1, resulting in inhibition of cyclin-dependent kinase activity necessary for phosphorylation of the tumor suppressor retinoblastoma protein. We further show that TIMP-1 modulation of cyclin D1 and p27KIP1 is achieved through TIMP-1-mediated differential regulation of protein stability independent of growth factor signaling. We also show that TIMP-1-mediated differential regulation of cyclin D1 and p27KIP1 is independent of cell adhesion signaling. Whereas approximately 50% of MCF10A cells with reduced TIMP-1 expression underwent cell death following loss of cell adhesion (anoikis), TIMP-1 overexpressing cells remained viable with prominent cell cycle arrest without detectable cell death. Taken together, we propose that TIMP-1-mediated cell survival independent of cell adhesion is accompanied with cell cycle arrest in human breast epithelial cells, although cell cycle regulation may not be a prerequisite for TIMP-1 regulation of apoptosis in general.

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Abbreviations

TIMP:

Tissue inhibitor of metalloproteinase

MMP:

matrix metalloproteinase

ECM:

extracellular matrix

CDKI:

cyclin-dependent kinase inhibitor

Rb:

retinoblastoma

ADAM:

a disintegrin and a metalloproteinase domain

AS:

antisense

mAb:

monoclonal antibody

pAb:

polyclonal antibody

rTIMP:

recombinant tissue inhibitor of metalloproteinase

FAK:

focal adhesion kinase

PI3-K:

phosphatidylinositol 3-kinase

ERKs:

extracellular signal-regulated kinases

EPA:

erythroid-potentiating activity

polyHEMA:

polyhydroxyethylmethacrylate

References

  • Alexander CM, Howard EW, Bissell MJ, Werb Z . (1996). J Cell Biol 135: 1669–1677.

  • Avalos BR, Kaufman SE, Tomonaga M, Williams RE, Golde DW, Gasson JC . (1988). Blood 71: 1720–1725.

  • Barcellos-Hoff MH, Aggeler J, Ram TG, Bissell MJ . (1989). Development 105: 223–235.

  • Bertaux B, Hornebeck W, Eisen AZ, Dubertret L . (1991). J Invest Dermatol 97: 679–685.

  • Chen J, Jackson PK, Kirschner MW, Dutta A . (1995). Nature 374: 386–388.

  • Damsky CH, Werb Z . (1992). Curr Opin Cell Biol 4: 772–781.

  • DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE, Taylor SM . (1992). Cancer Res 52: 701–708.

  • Docherty AJ, Lyons A, Smith BJ, Wright EM, Stephens PE, Harris TJ et al. (1985). Nature 318: 66–69.

  • Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA . (1993). Cell 73: 499–511.

  • Drubin DG, Nelson WJ . (1996). Cell 84: 335–344.

  • Dulbecco R, Allen WR, Bologna M, Bowman M . (1986). Cancer Res 46: 2449–2456.

  • Dulic V, Lees E, Reed SI . (1992). Science 257: 1958–1961.

  • Fata JE, Leco KJ, Moorehead RA, Martin DC, Khokha R . (1999). Dev Biol 211: 238–254.

  • Fowlkes JL, Enghild JJ, Suzuki K, Nagase H . (1994). J Biol Chem 269: 25742–25746.

  • Frisch SM, Francis H . (1994). J Cell Biol 124: 619–626.

  • Gasson JC, Golde DW, Kaufman SE, Westbrook CA, Hewick RM, Kaufman RJ et al. (1985). Nature 315: 768–771.

  • Golde DW, Bersch N, Quan SG, Lusis AJ . (1980). Proc Natl Acad Sci USA 77: 593–596.

  • Guedez L, Courtemanch L, Stetler-Stevenson M . (1998a). Blood 92: 1342–1349.

  • Guedez L, Stetler-Stevenson WG, Wolff L, Wang J, Fukushima P, Mansoor A et al. (1998b). J Clin Invest 102: 2002–2010.

  • Hatakeyama M, Brill JA, Fink GR, Weinberg RA . (1994). Genes Dev 8: 1759–1771.

  • Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K . (1992). FEBS Lett 298: 29–32.

  • Henriet P, Blavier L, Declerck YA . (1999). Apmis 107: 111–119.

  • Henriet P, Zhong ZD, Brooks PC, Weinberg KI, DeClerck YA . (2000). Proc Natl Acad Sci USA 97: 10026–10031.

  • Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA . (1992). Cell 70: 993–1006.

  • Juliano RL, Haskill S . (1993). J Cell Biol 120: 577–585.

  • Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S et al. (1992). Science 257: 1689–1694.

  • Lee SJ, Yoo HJ, Bae YS, Kim HJ, Lee ST . (2003). Biochem Biophys Res Commun 312: 1196–1201.

  • Lelievre S, Weaver VM, Bissell MJ . (1996). Recent Prog Horm Res 51: 417–432.

  • Li G, Fridman R, Kim HR . (1999). Cancer Res 59: 6267–6275.

  • Linette GP, Li Y, Roth K, Korsmeyer SJ . (1996). Proc Natl Acad Sci USA 93: 9545–9552.

  • Liotta LA, Steeg PS, Stetler-Stevenson WG . (1991). Cell 64: 327–336.

  • Liu XW, Bernardo MM, Fridman R, Kim HR . (2003). J Biol Chem 278: 40364–40372.

  • Liu XW, Taube ME, Jung KK, Dong Z, Lee YJ, Roshy S et al. (2005). Cancer Res 65: 898–906.

  • Luo Y, Hurwitz J, Massague J . (1995). Nature 375: 159–161.

  • Mazel S, Burtrum D, Petrie HT . (1996). J Exp Med 183: 2219–2226.

  • McCarthy K, Maguire T, McGreal G, McDermott E, O'Higgins N, Duffy MJ . (1999). Int J Cancer 84: 44–48.

  • Mohammed FF, Pennington CJ, Kassiri Z, Rubin JS, Soloway PD, Ruther U et al. (2005). Hepatology 41: 857–867.

  • Montgomery AM, Mueller BM, Reisfeld RA, Taylor SM, DeClerck YA . (1994). Cancer Res 54: 5467–5473.

  • Motokura T, Arnold A . (1993). Curr Opin Genet Dev 3: 5–10.

  • Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJ et al. (2002). J Biol Chem 277: 11069–11076.

  • O'Reilly LA, Huang DC, Strasser A . (1996). EMBO J 15: 6979–6990.

  • Porter JF, Shen S, Denhardt DT . (2004). Br J Cancer 90: 463–470.

  • Ree AH, Florenes VA, Berg JP, Maelandsmo GM, Nesland JM, Fodstad O . (1997). Clin Cancer Res 3: 1623–1628.

  • Roskelley CD, Desprez PY, Bissell MJ . (1994). Proc Natl Acad Sci USA 91: 12378–12382.

  • Schmidt JW, Piepenhagen PA, Nelson WJ . (1993). Semin Cell Biol 4: 161–173.

  • Schrohl AS, Holten-Andersen MN, Peters HA, Look MP, Meijer-van Gelder ME, Klijn JG et al. (2004). Clin Cancer Res 10: 2289–2298.

  • Sherr CJ, Roberts JM . (1995). Genes Dev 9: 1149–1163.

  • Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW et al. (1999). Cell 98: 137–146.

  • Toyoshima H, Hunter T . (1994). Cell 78: 67–74.

  • Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA . (1996). J Biol Chem 271: 10079–10086.

  • Wiseman BS, Sternlicht MD, Lund LR, Alexander CM, Mott J, Bissell MJ et al. (2003). J Cell Biol 162: 1123–1133.

  • Yoshiji H, Gomez DE, Thorgeirsson UP . (1996). Int J Cancer 69: 131–134.

  • Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T et al. (2002). Hepatology 36: 850–860.

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Acknowledgements

This work is supported by NIH/National Cancer Institute Grant CA89113 (to H-R CK).

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Authors and Affiliations

  1. Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    M E Taube, X-W Liu, R Fridman & H-R C Kim

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  1. M E Taube
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  2. X-W Liu
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  3. R Fridman
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  4. H-R C Kim
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Correspondence to H-R C Kim.

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Taube, M., Liu, XW., Fridman, R. et al. TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein. Oncogene 25, 3041–3048 (2006). https://doi.org/10.1038/sj.onc.1209336

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