Endoplazmik Retikulum Protein Kalite Kontrol Mekanizması Üyelerinde Varsayılan Androjen Cevap Elementlerinin Profillemesi

Amaç: Çalışmamızda endoplazmik retikulum protein-kalite kontrol mekanizması ile ilişkili genlerin promotor dizilerindeki varsayılan androjen cevap elementi bölgelerinin biyoinformatik araçlardan faydalanılarak in silico olarak analiz edilmesi amaçlanmıştır. Bu yol ile ER’deki protein-kalite kontrol mekanizmasının androjenler ile gerçekleşebilecek olası regülasyonunun tanımlanması ve prostat kanserindeki rolünün anlaşılması hedeflenmiştir. Materyal ve Metot: Endoplazmik Retikulum protein-kalite kontrol mekanizmasına ile ilişkili 29 hedef genin promotor dizileri University of California, Santa Cruz ve Eukaryotic Promotor Database veri tabanları kullanılarak belirlenmiştir. Tanımlanan bu diziler matinspector biyoinformatik aracına aktarılarak selektif transkripsiyon faktörü olarak çalışan androjen reseptörü ile DNA’nın etkileşimine aracılık ederek seçici transkripsiyon sürecine olanak sağlayan varsayılan androjen cevap elementi motifleri analiz adildi. İn silico analizler V$GREF benzeşim matrixi kullanılarak sürdürüldü. Bulgular: İn silico analiz sonuçlarımız Endoplazmik Retikulum protein kalite kontrol mekanizması ile ilişkili olarak incelediğimiz 29 adet genin promotor ve promotor bölge yakınında varsayılan androjen cevap elementi bölgelerinin bulunduğunu göstermiştir. Sonuç: Sonuçlarımız Endoplazmik Retikulum protein-kalite kontrol mekanizmasında yer alan proteinlerin androjen sinyal mekanizması aracılığıyla selektif olarak düzenlenebileceğini önermektedir. Olası bu regülasyon prostat kanseri gibi androjen sinyal iletiminin son derece kritik öneme sahip olduğu patolojilere ilişkin süreçlerin anlaşılabilmesine yol gösterici olacaktır. Her ne kadar biyoinformatik analizlerde varsayılan androjen cevap elementi bölgeleri tanımlanmış olsa da bu bölgelerin fonksiyonelliğine ilişkin ileri analizlerin gerçekleştirilmesine ihtiyaç duyulmaktadır.

Anahtar Kelimeler:

Endoplazmik Retikulum, Protein kalite kontrol mekanizması, Androjen Cevap Elementi, Prostat Kanseri, İn silico analiz

Profiling of Putative Androgen Response Elements in Endoplasmic Reticulum Protein Quality Control Mechanism Members

Aim: In our study, we aimed to in silico analyze the putative androgen response element regions in the promoter sequences of endoplasmic reticulum protein-quality control mechanism related genes by using bioinformatics tools. In this way, it is aimed to define the possible regulation with androgens of protein-quality control mechanism in the ER and to understand its role in prostate cancer. Material and Method: Promoter sequences of 29 target genes associated with the Endoplasmic Reticulum protein-quality control mechanism were determined using University of California, Santa Cruz ve Eukaryotic Promotor Databases. These sequences were transferred to the matinspector bioinformatics tool, and the putative androgen response element motifs that enable the selective transcription process by mediating the interaction of DNA with the androgen receptor, which works as a selective transcription factor, were analyzed. In silico analyzes was carried out using the V$GREF similarity matrix. Results: Our in silico analysis results showed that there were putative androgen response element regions of the 29 genes we examined in relation to endoplasmic reticulum protein-quality control mechanism components near the promoter and promoter region. Conclusion: Our results suggest that proteins that play a role in the endoplasmic reticulum protein-quality control mechanism might be selectively regulated by the androgen signaling mechanism. This possible regulation will be a guide to understanding the processes related to pathologies such as prostate cancer where androgen signal transduction is highly critical. Although putative androgen response element regions have been defined in bioinformatic analyzes, further analysis of the functionality of these regions is needed.

PDF

___

1. Schwarz DS, Blower MD. The endoplasmic reticulum: structure, function and response to cellular signaling. Cellular and molecular life sciences. 2016;73(1):79-94.
2. Rapoport TA. Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. Nature. 2007;450(7170):663-9.
3. Hegde RS, Ploegh HL. Quality and quantity control at the endoplasmic reticulum. Current opinion in cell biology. 2010;22(4):437-46.
4. Morito D, Nagata K. Pathogenic hijacking of ER-associated degradation: Is ERAD flexible? Molecular cell. 2015;59(3):335-44.
5. Guerriero CJ, Brodsky JL. The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiological reviews. 2012;92(2):537-76.
6. Araki K, Nagata K. Protein folding and quality control in the ER. Cold Spring Harbor perspectives in biology. 2011;3(11):a007526.
7. Christianson JC, Ye Y. Cleaning up in the endoplasmic reticulum: ubiquitin in charge. Nature structural & molecular biology. 2014;21(4):325-35.
8. Mehnert M, Sommer T, Jarosch E. ERAD ubiquitin ligases Multifunctional tools for protein quality control and waste disposal in the endoplasmic reticulum. BioEssays, 2010; 32 (10): 905-913.
9. Claessen JH, Kundrat L, Ploegh HL. Protein quality control in the ER: balancing the ubiquitin checkbook. Trends Cell Biol. 2012;22:22–32.
10. Bonifacino JS, Weissman AM. Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annu Rev Cell Dev Biol 14:19-57.
11. Needham PG, Brodsky JL. How early studies on secreted and membrane protein quality control gave rise to the ER associated degradation (ERAD) pathway: the early history of ERAD. Biochim Biophys Acta. 2013;1833(11):2447-57.
12. Scheper W, Hoozemans JJ. The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta neuropathologica. 2015;130(3):315- 31.
13. Adams J, Kauffman M. Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest. 2004;22(2):304-11.
14. Fribley A, Wang CY. Proteasome inhibitor induces apoptosis through induction of endoplasmic reticulum stress. Cancer Biol Ther. 2006;5(7):745-8.
15. Szokalska A, Makowski M, Nowis D, Wilczynski GM, Kujawa M, Wójcik C, et al. Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response. Cancer Res. 2009;69(10):4235-43.
16. Swami U, McFarland TR, Nussenzveig R, Agarwal N. Advanced Prostate Cancer: Treatment Advances and Future Directions. Trends Cancer. 2020;6(8):702-715.
17. Galani P. Diagnosis&Prognosis of Prostate Cancer. Journal of Advanced Medical and Dental Sciences Research. 2015;3(5):S49.
18. Cipolla BG, Mandron E, Lefort JM, Coadou Y, Della Negra E, Corbel L, et al. Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy. Cancer prevention research. 2015;8(8):712-9.
19. Peisch SF, Van Blarigan EL, Chan JM, Stampfer MJ, Kenfield SA. Prostate cancer progression and mortality: a review of diet and lifestyle factors. World journal of urology. 2017;35(6):867-74.
20. Brooke GN, Bevan C. The role of androgen receptor mutations in prostate cancer progression. Current genomics. 2009;10(1):18-25.
21. Gao W, Bohl CE, Dalton JT. Chemistry and structural biology of androgen receptor. Chemical reviews. 2005;105(9):3352-70.
22. Bennett NC, Gardiner RA, Hooper JD, Johnson DW, Gobe GC. Molecular cell biology of androgen receptor signalling. The international journal of biochemistry & cell biology. 2010;42(6):813-27.
23. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer cell. 2011;19(5):575-86.
24. Horie-Inoue K, Bono H, Okazaki Y, Inoue S. Identification and functional analysis of consensus androgen response elements in human prostate cancer cells. Biochemical and biophysical research communications. 2004;325(4):1312-7.
25. Shaffer PL, Jivan A, Dollins DE, Claessens F, Gewirth DT. Structural basis of androgen receptor binding to selective androgen response elements. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(14):4758-63.
26. Bolton EC, So AY, Chaivorapol C, Haqq CM, Li H, Yamamoto KR. Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev. 2007;21(16):2005-17.
27. Jariwala U, Prescott J, Jia L, Barski A, Pregizer S, Cogan JP, et al. Identification of novel androgen receptor target genes in prostate cancer. Mol Cancer. 2007;6:39.
28. Jin HJ, Kim J, Yu J. Androgen receptor genomic regulation. Transl Androl Urol. 2013;2(3):157-177.
29. Bastiaansen KC, Otero-Asman JR, Luirink J, Bitter W, Llamas MA. Processing of cell-surface signalling anti-sigma factors prior to signal recognition is a conserved autoproteolytic mechanism that produces two functional domains. Environmental microbiology. 2015;17(9):3263-77.
30. Friedlander R, Jarosch E, Urban J, Volkwein C, Sommer T. A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nature cell biology. 2000;2(7):379-84.
31. Tsai YC, Weissman AM. The unfolded protein response, degradation from the endoplasmic reticulum, and cancer. Genes & cancer. 2010;1(7):764-78.
32. Erzurumlu Y, Ballar P. Androgen mediated regulation of endoplasmic reticulum-associated degradation and its effects on prostate cancer. Sci Rep. 2017;7:40719.
33. Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, et al. DD3: A New Prostate-specific Gene, Highly Overexpressed in Prostate Cancer. Cancer research. 1999;59(23):5975-9.
34. Das I, Png CW, Oancea I, Hasnain SZ, Lourie R, Proctor M, et al. Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins. Journal of Experimental Medicine. 2013;210(6):1201-16.
Web Sayfaları Genomatix Software, MatInspector, Munich, Germany. Available from: http://www.genomatix.de/cgi-bin/eldorado/main.pl?s=8a065286baae1e0945d3d9294f299d6d;SELECTION=reg (Last accessed: October 2020)