Lenfoma-Lösemi Hücre Hatlarında Transkripsiyon Faktörü ELK-1 ve ELK-1 Hedef Genlerinin Ekspresyon Profili

Lösemide yeni moleküler belirteçlerin tanımlanması prognostik risk saptanması ve tedavinin belirlenmesinde gittikçe önem kazanmaktadır. Bu çalışmada, ELK-1 transkripsiyon faktörü ve potansiyel hedef genlerinin rolü Daudi, Jurkat, K-562 ve HL-60 hücre hatlarında araştırılmıştır. ELK-1, MCPIP, MCL-1, BCL- 10, CEBPB ve SRF gen ekspresyon profillerini değerlendirmek için Daudi, Jurkat, K- 562 ve HL-60 hücre hatlarında Gerçek-Zamanlı PZR analizi yapılmıştır. Daudi hücre hattında ELK-1 aşırı ekspresyonuna eşlik eden SRF artışı ve Jurkat hücrelerinde ise sadece ELK-1 artışı saptanmıştır. MCPIP, MCL-1, BCL-10 ve CEBPB genlerinin ekspresyonunun tüm hücre hatlarında kontrol grubuna kıyasla daha düşük olduğu saptanmıştır. ELK-1, BCL-10, CEBPB, MCL-1, MCPIP ve SRF'nin protein seviyeleri veya fosforilasyon durumu, ayrıca ELK-1 sürekli aşırı ekspresyonu sağlandığında veya bu hücre hatlarında tamamen susturulduğunda meydana gelebilecek değişiklikler değerlendirilmemiştir. Bu sorular gelecekteki çalışmalar için önerilmektedir.

Expression Profile of Transcription Factor ELK-1 and ELK-1 Target Genes on Lymphoma-Leukemia Cell Lines

Prognostic molecular markers identified in leukemia are becomingincreasingly important especially in risk stratification and to determine therapy. Inthis study, we investigate the role of ELK-1 transcription factor and its potentialtarget genes in four cell lines; Daudi, Jurkat, K-562 and HL-60. To evaluate ELK-1,MCPIP, MCL-1, BCL-10, CEBPB and SRF genes expression profiles we haveperformed a Real-time PCR analysis on Daudi, Jurkat, K-562 and HL-60 cell lines.ELK-1 over expression concomitant with SRF overexpression was detected only inDaudi cell line while only SRF overexpression was detected in jurkat cells.Expression of MCPIP, MCL-1, BCL-10 and CEBPB genes were decreased in all celllines. Protein levels or phosphorylation status of ELK-1, BCL-10, CEBPB, MCL-1,MCPIP and SRF, moreover, changes that may occur when ELK-1 continuousoverexpression is provided or completely silenced in these cell lines have not beenevaluated. These questions are suggestions for future investigations.

PDF

___

Walker A., Mrozek K., Kohlschmidt J., Rao K.W., Pettenati M.J., Sterling L.J., Marcucci G., Carroll A.J., Bloomfield C.D. 2013. New recurrent balanced translocations in acute myeloid leukemia and myelodysplastic syndromes: cancer and leukemia group B 8461, Genes, Chromosomes and Cancer 52(4), 385-401.
Shaffer L.G. 2013. Microarray - Based Cytogenetics in: S.L. Gersen, M.B. Keagle (Eds.) The Principles of Clinical Cytogenetics, Springer Science+Business Media, New York.
Yasar D., Karadogan I., Alanoglu G., Akkaya B., Luleci G., Salim O., Timuragaoglu A., Toruner G.A., Berker-Karauzum S. 2010. Array comparative genomic hybridization analysis of adult acute leukemia patients, Cancer Genetics and Cytogenetics, 197(2), 122-129.
Boros J., O'Donnell A., Donaldson I.J., Kasza A., Zeef L., Sharrocks A.D. 2009. Overlapping promoter targeting by Elk-1 and other divergent ETS-domain transcription factor family members, Nucleic Acids Research, 37(22), 7368- 7380.
Boros J., Donaldson I.J., O'Donnell A., Odrowaz Z.A., Zeef L., Lupien M., Meyer C.A., Liu X.S., Brown M., Sharrocks A.D. 2009. Elucidation of the ELK1 target gene network reveals a role in the coordinate regulation of core components of the gene regulation machinery, Genome Research, 19(11), 1963-1973.
Cohen-Armon M. 2007. PARP-1 activation in the ERK signaling pathway, TRENDS in Pharmacological Sciences, 28(11), 556-560.
Posern G., Treisman R. 2006. Actin' together: serum response factor, its cofactors and the link to signal transduction, Trends in Cell Biology, 16(11), 588-96.
Schmeier S., MacPherson C.R., Essack M., Kaur M., Schaefer U., Suzuki H., Hayashizaki Y., Bajic V.B. 2009. Deciphering the transcriptional circuitry of microRNA genes expressed during human monocytic differentiation, BMC Genomics 10, 595.
Wagner E.F., Nebreda A.R. 2009. Signal integration by JNK and p38 MAPK pathways in cancer development, Nature Reviews Cancer, 9(8), 537-49.
McCormick F. 2011. Cancer therapy based on oncogene addiction, Journal of Surgical Oncology, 103(6), 464-7.
Zhang R., Kim Y.M., Lu X., Wang X., Pang H., Li Y., Li S., Lee J.Y. 2011. Characterization of a novel t(2;5;11) in a patient with concurrent AML and CLL: a case report and literature review, Cancer Genetics 204(6), 328-33.
Maicas M., Vazquez I., Vicente C., Garcia-Sanchez M.A., Marcotegui N., Urquiza L., Calasanz M.J., Odero M.D. 2013. Functional characterization of the promoter region of the human EVI1 gene in acute myeloid leukemia: RUNX1 and ELK1 directly regulate its transcription, Oncogene, 32(16), 2069-78.
Gade P., Roy S.K., Li H., Nallar S.C., Kalvakolanu D.V. 2008. Critical role for transcription factor C/EBP-beta in regulating the expression of death-associated protein kinase 1, Molecular and Cellular Biology, 28(8), 2528-2548.
Uehata T., Akira S. 2013. mRNA degradation by the endoribonuclease Regnase- 1/ZC3H12a/MCPIP-1, Biochimica et Biophysica Acta 1829(6-7), 708-713.
Liang J., Saad Y., Lei T., Wang J., Qi D., Yang Q., Kolattukudy P.E., Fu M. 2010. MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-kappaB signaling, The Journal of Experimental Medicine, 207(13), 2959-2973.
Cifuentes R.A., Cruz-Tapias P., Rojas-Villarraga A., Anaya J.M. 2010. ZC3H12A (MCPIP1): molecular characteristics and clinical implications, Clinica Chimica Acta 411(23-24), 1862-1868.
Kasza A., Wyrzykowska P., Horwacik I., Tymoszuk P., Mizgalska D., Palmer K., Rokita H., Sharrocks A.D., Jura J. 2010. Transcription factors Elk-1 and SRF are engaged in IL1- dependent regulation of ZC3H12A expression, BMC Molecular Biology, 11, 14.
Townsend K.J., Zhou P., Qian L., Bieszczad C.K., Lowrey C.H., Yen A., Craig R.W. 1999. Regulation of MCL1 through a serum response factor/Elk-1- mediated mechanism links expression of a viability-promoting member of the BCL2 family to the induction of hematopoietic cell differentiation, The Journal of Biological Chemistry, 274(3), 1801-1813.
Schimmer A.D., Hedley D.W., Penn L.Z., Minden M.D. 2001. Receptor- and mitochondrialmediated apoptosis in acute leukemia: a translational view, Blood 98(13), 3541-3553.
Shih L.Y., Fu J.F., Shurtleff S.A., Morris S.W., Downing J.R. 2001. Lack of BCL10 mutations in multiple myeloma and plasma cell leukemia, Genes Chromosomes Cancer, 30(4), 402-406.
VanGuilder H.D., Vrana K.E., Freeman W.M. 2008. Twenty-five years of quantitative PCR for gene expression analysis, Biotechniques, 44(5), 619-626.
Sharrocks A.D. 2002. Complexities in ETSdomain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture, Biochemical Society Transactions, 30(2), 1-9.
Eilersi, P.H., de Menezes R. X. 2005. Quantile smoothing of array CGH data, Bioinformatics 21(7), 1146–1153.