Nurullah KEKLİKOĞLU, Meltem KORAY, İlker BOLAT, Sevtap AKINCI, Nurullah KEKLİKOĞLU

AKTİVATOR PROTEİN-1’İN ETKİSİNİ KULLANARAK ONKOJENİK TRANSFORMASYONU YÖNLENDİRMEK

Bir uyarıyla karşılaşan hücrelerde, uyarana ilk yanıt veren genler IEG (Immediate Early Gene) grubundaki genlerdir. Bu genler hücre büyümesi, çoğalması, farklılaşması ve hücrenin programlanmış ölümü (apoptozis) ile ilgili transkripsiyon faktörleridir. Bir IEG olan c-fos geninin ürettiği Fos proteinleri, yine bir IEG olan c-jun geninin ürettiği Jun proteinleri transkripsiyon faktör kompleksi Aktivator Protein-1 (AP-1)’in komponentleri olarak birlikte işlev görürler. AP-1 kompleksinin üyeleri farklı gen ekspresyonlarını ve büyüme faktörlerine hücresel yanıtın bazı yönlerini düzenlerler. Bu komponentler büyüme, çoğalma, farklılaşma, programlanmış hücre ölümü ve onkojenik transformasyon gibi hücresel süreçlerde kilit rolü oynarlar. Karsinogenezin, IEG ve AP-1 tarafından kontrol edilen hücresel süreçlerdeki bozukluğun bir sonucu olduğu tanımlanmıştır. IEG ve AP-1’in hücrelerdeki normal ekspresyonlarının yaşamsal önemi vardır ancak anormal ekspresyonları, onkojenik transformasyon gibi ciddi sorunlar doğurur. AP-1’in ekspresyonunu artıran veya azaltan maddeler ve etkenler konusundaki çalışmalar devam etmektedir. Onkojenik transformasyonun aşamaları ve bu transformasyonda IEG ve AP-1’in rolü tam olarak aydınlatılabilirse karsinogenez kontrol edilebilir bir duruma gelebilecek hatta kanser hücrelerinin bazı özelliklerinden çeşitli hastalıkların tedavisinde yararlanılabilecektir.

Anahtar Kelimeler:

IEG, AP-1, Karsinogenez, Protoonkojenler, Onkoproteinler, Onkojenik transformasyon

PDF

___

Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 1987;49:729-739.
Angel P, Karin M . The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochem Biophys Acta 1991;1072:129-157.
Anisimov VN. Biology of aging and cancer. Cancer Control 2007;14:23-31.
Bakiri L, Matsuo K, Wisniewvska M, Wagner EF, Yaniv M. Promoter specificity and biological activity of tethered AP-1 dimers. Mol Cell Biol 2002;22:4952-4964.
Bossis G, Malnou CE, Farras R, Andermarcher E, Hipskind R, Rodriguez M, Schmidt D, Muller S, Jariel-Encontre I, Piechaczyk M. Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol 2005;25:6964-6979.
Chun KS, Kim SH, Song YS, Surh YJ. Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin. Carcinogenesis 2004;25:713-722.
Clayton DF. The genomic action potential. Neurobiol Learn Mem. 2000;74:185-216.
Crighton D, Ryan KM. Splicing DNA-damage responses to tumour cell death. Biochim Biophys Acta 2004;1705:3-1715.
Ding M, Huang C, Lu Y, Bowman L, Castranova V, Vallyathan V. Involvement of protein kinase C in crystalline silicainduced activation of the MAP kinase and AP-1 pathway. Am J Physiol Lung Cell Mol Physiol 2006;290:291-297.
Dong Z., Birer MJ, Watts RG, Matrisian LM, Colburn NH. Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells. Proc Natl Acad Sci USA 1994;91:609–613.
Eferl R, Wagner EF. AP-1: A double-edged sword in tumorigenesis. Nat Rev Cancer 2003;3:859-868.
Fleischmann A, Hafezi F, Elliott C, Reme EC, Rüther U, Wagner FE. Fra-1 replaces c-Fos-dependent functions in mice. Genes & Dev 2000;14:2695-2700.
Foletta VC. Transcription factor AP-1, and the role of Fra-2. Immunol Cell Biol 1996;74: 121-133.
Franchi A, Calzolari A, Zampi G. Immunohistochemical detection of c-fos and c-jun expression in osseous and cartilaginous tumours of the skeleton. Virchows Arch. 1998;432:515-519.
Funk JO. Cancer cell cycle control. Anticancer Res 1999;19:4772-4780.
Glover JNM, Harrison SC. Crystal structure of the Heterodimeric bZIP Transcription Factor c-Fos/ c-Jun Bound to DNA. Nature 1995;373:257-261.
Greenhalgh DA, Wang XJ, Eckhardt JN, Roop DR. 12-Otetradecanoylphorbol-13-acetate promotion of transgenic mice expressing epidermal-targeted v-fos induces rasHA-activated papillomas and carcinomas without p53 mutation: association of v-fos expression with promotion and tumor autonomy. Cell Growth Differ 1995;6:579-586.
Hennigan RF, Stambrook PJ. Dominant negative c-jun inhibits activation of the cyclin D1 and cyclin E kinase complexes. Mol Biol Cell 2001;12:2352-2363.
Hou DX, Kai K, Li JJ, Lin S, Terahara N, Wakamatsu M, Fujii M, Young MR, Colburn N. Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure-activity relationship and molecular mechanisms. Carcinogenesis 2004;25:29-36.
Huang Q, Shen HM, Ong CN. Inhibitory effect of emodin on tumor invasion through suppression of activator protein-1 and nuclear factor-kappaB. Biochem Pharmacol 2004;68:361-371.
Jansen AP, Camalier CE, Colburn NH. Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Cancer Res 2005;65:6034-6041.
Jin C, Li H, Murata T, Sun K, Horikoshi M, Chiu R, Yokoyama KK. JDP2, a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic acid-induced differentiation of F9 cells. Mol Cell Biol 2002;22:4815-4826.
Jochum W, Passegue E, Wagner EF. AP-1 in mouse development and tumorigenesis. Oncogene 2001;20:2401_2412.
Kang JS, Yoon YD, Lee KH, Park SK, Kim HM. Costunolide inhibits interleukin-1beta expression by down-regulation of AP-1 and MAPK activity in LPS-stimulated RAW 264.7 cells. Biochem Biophys Res Commun 2004;313:171-177.
Karin M, Zhend-gang L, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol 1997;9:240-246.
Keklikoglu N. The localization of Fos B, a member of transcription factor AP-1 family, in rat odontoblasts and pulpal undifferentiated ectomesenchymal cells. Folia Histochem Cytobiol 2004;42:191-193.
Lee CS, Charalambous D. Immunohistochemical localisation of the c-fos oncoprotein in pancreatic cancer. Zentralbl Pathol 1994;140:271-275.
Lee SO, Jeong YJ, Im HG, Kim CH, Chang YC, Lee IS. Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells. Biochem Biophys Res Commun 2007;354:165-171.
Lin S, Li JJ, Fujii M, Hou DX. Rhein inhibits TPA-induced activator protein-1 activation and cell transformation by blocking the JNK-dependent pathway. Int J Oncol 2003;22:829-833.
Liu Y, Lu C, Shen Q, Munoz-Medellin D, Kim H, Brown PH. AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1cyclin expression and reducing cyclin-dependent kinase activity. Oncogene 2004;23:8238-8246.
Liu Y, Ludes-Meyers J, Zhang Y, Munoz-Medellin D, Kim HT, Lu C, Ge G, Schiff R, Hilsenbeck SG, Osborne CK, Brown PH. Inhibition of AP-1 transcription factor causes blockade of multiple signal transduction pathways and inhibits breast cancer growth. Oncogene 2002;21:7680-7689.
Lorenzini A, Tresini M, Mawal-Dewan M, Frisoni L, Zhang H, Allen RG, Sell C, Cristofalo VJ. Role of the Raf/MEK/ERK and the PI3K/Akt(PKB) pathways in fibroblast senescence. Exp Gerontol 2002;37:1149-1156.
Lu C, Shen Q, Dupre E, Kim H, Hilsenbeck S, Brown PH. cFos is critical for MCF-7 breast cancer cell growth. Oncogene 2005;24:6516-6524.
Ludes-Meyers JH, Liu Y, Munoz-Medellin D, Hilsenbeck SG, Brown PH. AP-1 blockade inhibits the growth of normal and malignant breast cells. Oncogene 2001;20:2771-2780.
Milde-Langosch K. The Fos family of transcription factors and their role in tumourigenesis. Eur J Cancer 2005;41:2449-2461.
Pitot HC. Multistage carcinogenesis--genetic and epigenetic mechanisms in relation to cancer prevention. Cancer Detect Prev 1993;17:567-573.
Qi X, Borowicz S, Pramanik R, Schultz RM, Han J, Chen G. Estrogen receptor inhibits c-Jun-dependent stress-induced cell death by binding and modifying c-Jun activity in human breast cancer cells. J Biol Chem 2004;279:6769-6777.
Rajapakse N, Kim MM, Mendis E, Huang R, Kim SK. Carboxylated chitooligosaccharides (CCOS) inhibit MMP-9 expression in human fibrosarcoma cells via down-regulation of AP-1. Biochim Biophys Acta 2006;1760:1780-1788.
Ramirez CJ, Haberbusch JM, Soprano DR, Soprano KJ. Retinoic acid induced repression of AP-1 activity is mediated by protein phosphatase 2A in ovarian carcinoma cells. J Cell Biochem 2005;96:170-182.
Redell MS, Tweardy DJ. Targeting transcription factors for cancer therapy. Curr Pharm Des 2005;11:2873-2887.
Roche E, Buteau J, Aniento I, Reig JA, Soria B, Prentki M. Palmitate and oleate induce the immediate-early response genes c-fos and nur-77 in the pancreatic beta-cell line INS1. Diabetes 1999;48:2007-2014.
Shah SA, Volkov Y, Arfin Q, Abdel-Latif MM, Kelleher D. Ursodeoxycholic acid inhibits interleukin 1 beta [corrected] and deoxycholic acid-induced activation of NF-kappaB and AP-1 in human colon cancer cells. Int J Cancer 2006;118:532-539.
Sheerin A, Thompson KS, Goyns MH. Altered composition and DNA binding activity of the AP-1 transcription factor during the ageing of human fibroblasts. Mec Ageing Dev 2001;122:1813-1824.
Shirsat NV, Shaikh SA. Overexpression of the immediate early gene fra-1 inhibits proliferation, induces apoptosis, and reduces tumourigenicity of c6 glioma cells. Exp Cell Res 2003;291:91-100.
Stewart SA. Telomere maintenance and tumorigenesis: an "ALT"ernative road. Curr Mol Med 2005;5:253-257.
de Sousa SO, Mesquita RA, Pinto DS Jr, Gutkind S. Immunolocalization of c-Fos and c-Jun in human oral mucosa and in oral squamous cell carcinoma. J Oral Pathol Med 2002;31:78-81.
Tresini M, Lorenzini A, Frisoni L, Allen RG, Cristofalo VJ. Lack of Elk-1 phosphorylation and dysregulation of the extracellular regulated kinase signaling pathway in senescent human fibroblast. Exp Cell Res 2001;269:287-300.
Wang Y, Li Y, Qi X, Yuan W, Ai J, Zhu C, Cao L, Yang H, Liu F, Wu X, Liu M. TRIM45, a novel human RBCC/TRIM protein, inhibits transcriptional activities of ElK-1 and AP-1. Biochem Biophys Res Commun 2004:8;323:9-16.
Wu Q, Chen Z, Su W. Mechanism of inhibition on activator protein-1 activity by all-trans retinoic acid in gastric cancer cells. Chin Med J (Engl) 2000;113:972-976.
Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana BK, Hunziker R, Colburn N. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci U S A. 1999 ;96:9827-9832.
Yuksel M, Okajima K, Uchiba M, Okabe H. Gabexate mesilate, a synthetic protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappaB and activator protein-1 in humanmonocytes. J Pharmacol Exp Ther 2003;305:298-305.
Zhang Z, Li M, Rayburn ER, Hill DL, Zhang R, Wang H. Oncogenes as Novel Targets for Cancer Therapy (Part III): Transcription Factors. Am J Pharmacogenomics 2005;5:327-338.