Abstract
S100A4 is a cell proliferation- and cancer metastasis-related gene. Previous studies have shown that over-expression of S100A4 drives the cells into the S-phase of the cell cycle, with concomitant enhancement of p53 detection. This has led to the postulate that S100A4 could be controlling cell cycle progression by sequestering p53 and abrogating its G1-S checkpoint control. Cells induced by S100A4 to enter the S-phase do successfully negotiate the G2-M checkpoint control. Here we show that S100A4 is also involved in the regulation of control at this checkpoint. Stathmin is known to be associated, together with p53 in controlling G2-M transition. We present evidence that the expression of S100A4 and stathmin genes is up regulated in exponentially growing HeLa cells. They are down regulated in parallel when cell proliferation is inhibited by hyperthermia and 4-hydroxynonenal (4-HNE). We postulate that S100A4 might directly induce stathmin up regulation to enable cells to enter into mitosis. Since wild-type p53 is known to down regulate stathmin expression, we further postulate this might also involve S100A4-mediated sequestration of p53. The expression of heme oxygenase (HO-1), a stress-response protein, has been used to monitor effects of hyperthermia, 12-O-tetradecanoly phorbol 13-acetate (TPA) and 4-HNE. All these treatments induced HO-1 and also when cells growing in serum-deficiency were restored with full serum. HO-1 induction occurred irrespective of S100A4 expression status. HO-1 gene has responsive elements for many angiogenic agents and induces marked neovascularisation of tumours. We suggest therefore that S100A4 may not possess angiogenic properties.
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Sherbet GV, Parker C, Usmani BA, Lakshmi MS. Epidermal growth factor receptor status correlates with cell proliferation related 18A2/mts1 gene expression in human carcinoma cell lines. Ann NY Acad Sci 1995; 768: 272–6.
Parker C, Whittaker PA, Usmani B et al. Induction of 18A2/mts1 gene expression and its effects on metastasis and cell cycle control. DNA Cell Biol 1994; 13: 1021–28.
Albertazzi E, Cajone F, Lakshmi MS, Sherbet GV. Heat shock modulates the expression of the metastasis related mts1 gene and cell proliferation of murine and human cancer cells. DNA Cell Biol 1998;17: 1–7.
Spector NL, Mehlen P, Ryan C et al. Regulation of the 28 kDa heat shock protein by retinoic acid during differentiation of human leukaemic HL-60 cells. FEBS Lett 1994; 337: 184–8.
Spector NL, Ryan C, Samson W et al. Heat shock protein is a unique marker of growth arrest during macrophage differentiation of HL-60 cells. J Cell Physiol 1993; 156: 619–25.
Spector NL, Samson W, Ryan C et al. Growth arrest of human lymphocytes B is accompanied by induction of the low molecular weight mammalian heat shock protein (HSP28). J Immunol 1992; 148: 1668-73.
Honore B, Rasmussen HH, Celis A et al. The molecular chaperones HSP28, GRP78, endoplasmin and calnexin exhibit strikingly different levels in quiescent keratinocytes as compared to their proliferating normal and transformed counterparts. cDNA cloning and expression of calnexin. Electrophoresis 1994; 15: 482–90.
Parker C, Lakshmi MS, Piura B Sherbet GV. Metastasis associated mts1 gene expression correlates with increased p53 detection in B16 murine melanoma. DNA Cell Biol 1994; 13: 343-51.
Michalowitz D, Halevy O, Oren M. Conditional inhibition of transformation and cell proliferation by a temperature sensitive mutant of p53. Cell 1990; 62: 671-80.
Stewart N, Hicks GG, Paraskevas F, Mowat M. Evidence for a second cell cycle block at G2/M by p53. Oncogene 1995; 10: 109–15.
Pellegata NS, Antoniono RJ, Redpath JL, Stanbridge EJ. DNA damage and p53-mediated cell cycle arrest: A re-evaluation. Proc Natl Acad Sci USA 1996; 93: 15209–14.
Luo XN, Mookerjee B, Ferrari A et al. Regulation of phosphoprotein P18 in leukaemia cells. Cell cycle-regulated phosphorylation by p34 (cdc2) kinase. J Biol Chem 1994; 269: 10312–8.
Rowlands DC, Harrison RF, Jones NA et al. Stathmin is expressed by proliferating hepatocytes during liver regeneration. J Clin Pathol 1995; 48: M88–92.
Friedrich B, Gronberg H, Landstrom M et al. Differentiation-stage specific expression of oncoprotein-18 in human and rat prostatic adenocarcinoma. Prostate 1995; 27: 102–9.
Bieche I, Lackhar S, Becette V et al. Over-expression of the stathmin gene in a subset of human breast cancer. Br J Cancer 1998; 78: 701–9.
Ahn J, Murphy M, Kratowicz S et al. Down-regulation of the stathmin/ Op18 and FKB25 genes following p53 induction. Oncogene 1999; 18: 5954–8
Marklund U, Larsson N, Gradin HM et al. Oncoprotein-18 is a phosphorylation responsive regulator of microtubule dynamics. EMBO J 1995; 15: 5290–8.
DiPaolo G, Antonsson B, Kassel D et al. Phosphorylation regulates he microtubule-destabilising activity of stathmin and its interaction with tubulin. FEBS Lett 1997; 416: 149-52.
Andersen SSL, Ashford J, Tournebize R et al. Mitotic chromatin regulates phosphorylation of stathmin/Op-18. Nature 1997; 389: 640–643.
Curmi PA, Anderson SSL, Lachkar S et al. The stathmin/tubulin interaction in vitro. J Biol Chem 1997; 272: 25029–36.
Curmi PA, Gavet O, Charbaut E, Ozon S. Stathmin and its phosphoprotein family. General properties, biochemical and functional interaction with tubulin. Cell Struct Funct 1999; 24: 45–57.
Albertazzi E, Cajone F, Leone BE et al. Expression of metastasisassociated genes h-mts1 (S100A4) and nm23, in carcinoma of the breast is related to disease progression. DNA Cell Biol 1998; 17: 335–42.
Keyse SM, Tyrell RM. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide and sodium arsenite. Proc Natl Acad Sci USA 1989; 86: 9–103.
Barrera G, Pizzimenti S, Muraca R et al. Effect of 4-hydroxynonenal on cell cycle progression in HL-60 cells. Free Radical Biol Med 1996; 20: 455–62.
Eustace W, Johnson B, Jones NA et al. Down regulation but not phosphorylation of stathmin is associated with induction of HL-60 cell growth arrest and differentiation by physiological agents. FEBS Lett 1995; 364: 309–13.
Jones NA, Rowlands DC, Johnson WEB et al. Persistent growth of Balb/C mouse plasmacytoma and human myeloma cell lines in the presence of phorbol myristate acetate is associated with the continued expression of OP18 (stathmin). Haematol Oncol 1995; 13: 29–43.
Marklund U, Osterman O, Melander H et al. The phenotype of a cdc2 kinase target site-deficient mutant of oncoprotein-18 reveals a role of this protein in cell cycle control. J Biol Chem 1994; 269: 30626–35.
Larsson N, Melander H, Marklund U et al. G2/M transition requires multisite phosphorylation of oncoprotein-18 by two distinct protein kinase systems. J Biol Chem 1995; 270: 14175–83.
Duraj J, Kovcikova M, Sedlak J et al. The protein kinase C inhibitor blocks phosphorylation of stathmin during TPA-induced growth inhibition of human pre-B leukaemia REH6 cells. Leukaemia Res 1995; 19: 457–61.
Beretta L, Dubois MF, Sobel A, Bensaude O. Stathmin is a major substrate for mitogen-activated protein kinase during heat shock and chemical stress in HeLa cells. Eur J Biochem 1995 227: 388–95.
Lawler S, Gavet O, Rich T, Sobel A. Stathmin over-expression in 293 cells affects signal transduction and cell growth. FEBS Lett 1998; 421: 55–60.
Choi AMK, Alam J. Heme oxygenase-1. Function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Amer J Respiratory Cell Mol Biol 1996; 15: 9–19.
Ito H, Hasegawa K, Inaguma Y et al.Modulation of the stress-induced synthesis of stress proteins by a phorbol ester and okadaic acid. J Biochem 1995; 118: 629-634.
Jacquiersarlin MR, Jornot L, Polla BS. Differential expression and regulation of HSP70 and HSP90 by phorbol esters and heat shock. J Biol Chem 1995; 270: 1494–9.
Mehlen P, Arrigo P. The serum-induced phosphorylation of mammalian HSP27 correlates with changes in its intracellular localization and levels of oligomerisation. Eur J Biochem 1994; 221:327–34.
Hosoya H, Ishikawa K, Dohi N, Marunouchi T. Transcriptional and post-transcriptional regulation of PR22 (Op18) with proliferation control. Cell Structure Function 1996; 21: 237–43.
Cajone F, Bernelli-Zazzera A. The action of 4-hydroxynonenal on heat shock gene expression in cultured hepatoma cells. Free Radical Res Commun 1989; 7: 189–94.
Cajone F, Salina M, Bernelli-Zazzera A. 4-hydroxynonenal induces a DNA-binding protein similar to the heat shock factor. Biochem J 1989; 162:977–9.
Allevi P, Anastasia M, Cajone F et al. Structural requirements of aldehydes produced in LPO for the activation of heat shock genes in HeLa cells. Free Radical Biol Med 1995; 18: 107–16.
Ambartsumian NS, Grigorian MS, Larsen IF et al.Metastasis of mammary carcinomas in GRS/A hybrid mice transgenic for the mts1 gene. Oncogene 13: 1621-30.
Davies MPA, Rudland PS, Robertson L et al. Expression of the calcium-binding protein S100A4 (p9Ka) in MMTV-neu transgenic mice induces metastasis of mammary tumours. Oncogene 1996; 13: 1631–7.
Maelandsmo GM, Hovig E, Skrede M et al. Reversal of the in vivo metastatic phenotype of human tumour cells by an anti-CAPL (mts1) ribozyme. Cancer Res 1996; 56: 5490-8.
Takenaga K, Nakamura Y, Endo H, Sakiyama S. Involvement of S100-related calcium binding protein pEL98 (mts1) in cell motility and tumour cell invasion. Jap J Cancer Res 1994; 85: 831–9.
Takenaga K, Nakanishi H, Wada K et al. Increased expression of S100A4, a metastasis associated gene in human colorectal adenocarcinoma. Clin Cancer Res 1997; 3: 2309–16.
Lloyd BH, Platt-Higgins A, Rudland PS, Barraclough R. Human S100A4 (p9Ka) induces the metastatic phenotype upon benign tumour cells. Oncogene 1998; 17: 465–473.
Chiaramonte R, Fasola S, Lollini PL et al. Is mts1 (S100A4) gene involved in the metastatic process modulated by gamma interferon?. Pathobiology 1998; 66: 38–40.
Sherbet GV, Lakshmi MS. The Genetics of Cancer, Academic Press, London 1997.
Deramaudt BMJM, Braunstein S, Remy P, Abraham NG. Gene transfer of human heme oxygenase into coronary endothelial cells potentially promotes angiogenesis. J Cell Biochem 1998; 68: 121–7.
Camhi SL, Alam J, Choi AMK. Transcriptional activation of the mouse heme oxygenase gene (HO-1) by interleukin-6 requires cooperation between 5? distal enhancer and the proximal promoter. Amer J Respiratory Critical Care Med 1996; 153: A29.
Camhi SL, Alam J, Otterbein I et al. Induction of heme oxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation. Amer J Respiratory Cell Mol Biol 1995; 13: 387–98.
Kozumi T, Odani N, Okuyama T et al. Identification of a cisregulatory element for ?12-prostaglandin J2-induced expression of the rat heme oxygenase gene. J Biol Chem 1995; 270: 21779–84
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Cajone, F., Sherbet, G. Stathmin is involved in S100A4-mediated regulation of cell cycle progression. Clin Exp Metastasis 17, 865–871 (1999). https://doi.org/10.1023/A:1006778804532
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DOI: https://doi.org/10.1023/A:1006778804532