Erad'ın androjen temelli hormonal regülasyonunun ve bu regülasyonun prostat kanseri gelişimindeki rolünün araştırılması
Yükleniyor...
Tarih
2018
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Ege Üniversitesi, Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Ökaryotik hücrelerde total proteomun üçte birinin sentezi endoplazmik retikulum (ER)'da gerçekleşmektedir. Yeni sentezlenen proteinlerin olgun formlarına katlanmaları ER'de oldukça sıkı regüle edilen "protein kalite kontrol" mekanizması tarafından kontrol edilmektedir. Mutasyonlar, genotoksik etkiler veya hücresel stres nedeniyle nihai formuna ulaşamayan proteinlerin, ER'den çıkıp fonksiyon gösterdikleri yere ulaşmalarını engellemek için öncelikle bu proteinler tekrarlayan katlanma sürecine dahil edilirler. Yine de düzgün şekilde katlanamayan proteinler, ER ilişkili protein yıkım (ERAD) yolağı adı verilen mekanizma aracılığıyla tanınıp, ubikitinasyona uğratılarak 26S proteozomda yıkıma sevk edilirler. Aynı zamanda ERAD'ın fizyolojik şartlar altında normal birçok proteinin endojen seviyelerini düzenlediği de bilinmektedir. Kompleks bir süreç olan ERAD yolağında; kanal proteinleri, şaperonlar, ubikitinasyonda rol oynayan E1, E2, E3 enzimleri, retrotranslokasyondan sorumlu motor proteinleri ve sürece eşlik eden kofaktörler gibi birçok anahtar molekül senkronize şekilde görev almaktadır. ERAD'ın regülasyonunda ubikitin ligazların ve onların oluşturduğu dinamik ERAD komplekslerinin, katlanmamış protein yanıtı (UPR) yolağının ve endojen ERAD inhibitör proteininin rol oynadığı bilinmektedir. Androjen aracılı gen ifadelerindeki değişimlerin incelendiği bir LONG-SAGE kütüphane taramasında androjen uygulaması sonrası ERAD inhibitör proteini SVIP ifadesinin azaldığı bildirilmiş ancak regülasyona ilişkin detaylı bilgi paylaşılmamıştır. Buradan yola çıkarak ERAD'ın androjenler ile regüle olabileceği hipotezi ortaya atılmış olup, ERAD'ın androjenler aracılı regülasyonunun incelenmesi hedeflenmiştir. Bu doktora tezi kapsamında ERAD'ın androjenler aracılı regülasyonu karakterize edilerek, bu regülasyonun doğrudan androjen reseptörü (AR) aracılığıyla gerçekleştiği belirlenmiştir. AR sinyalizasyonunun prostat kanseri gelişiminde önemli roller oynadığı bilinmektedir. Gerçekleştirilen fonksiyonel testler ile ERAD üyelerinin prostat kanseri hücrelerinde üstlenmiş oldukları roller incelenmiştir. ERAD'ın prostat kanseri hücrelerinin proliferatif, migratif ve malin transformasyon yeteneklerinin düzenlenmesinde önemli bir role sahip olduğu belirlenmiştir. Ortaya koyduğumuz veriler ERAD'ın prostat kanseri gelişiminde ve prostat kanserinin tedavisinde hedef alınması gereken bir mekanizma olabileceğini önermektedir. Sonuç olarak projemizin sonuçları hem literatüre hem yeni projelerin oluşumuna hem de potansiyel terapötik yaklaşımların dizaynına ışık tutacaktır.
In eukaryotic cells synthesis of one third of total proteome occurs in the Endoplasmic Reticulum (ER). The folding of of newly synthesized proteins to mature forms is controlled by the "protein quality control" mechanism, which is tightly regulated in the ER. The proteins that can not reach the final form due to mutations, genotoxic effects or cellular stress are firstly incorporated into the repetitive folding process in order to prevent arrival to their functional site. Nonetheless, proteins that can not fold properly, are transported to 26S proteasome for degradation via recognition and ubiqitination by a mechanism known as as ER-associated protein degradation (ERAD) pathway. It is also known that ERAD regulates endogenous levels of many normal proteins under physiological conditions. Many key molecules such as channel proteins, chaperones, E1-E2-E3 enzymes involved in ubiquitination, motor proteins responsible for retrotranscription, and cofactors accompanying the process are in sync with each other In ERAD. It is known that ubiquitin ligases and their dynamic ERAD complexes, unfolded protein response (UPR) and endogenous ERAD inhibitor protein play a role in the regulation of ERAD. The ERAD inhibitor protein SVIP expression has been reported to decrease after androgen administration in a LONG-SAGE library screening examined the androgen-mediated changes in gene expression, however no detailed information on regulation has been reported. From this, we hypothesized that ERAD could be regulated by androgens and aimed to examine ERAD-mediated regulation of androgens in our project. Within this PhD thesis, the regulation of ERAD through androgens was characterized and it was determined that the regulation of ERAD is mediated by direct regulation of the androgen receptor (AR). It is known that AR signalization plays an important role in the development of prostate cancer. The roles of ERAD members in prostate cancer cells were examined by functional tests. ERAD has been shown to have an important role in regulation of proliferative, migratory and malignant transformation abilities of prostate cancer cells. The data, we have revealed, suggests that ERAD may be a mechanism to be targeted in the development of prostate cancer and in the treatment of prostate cancer. In conclusion, the results of our project will shed light on both literature and the formation of new projects and also the design of potential therapeutic approaches.
In eukaryotic cells synthesis of one third of total proteome occurs in the Endoplasmic Reticulum (ER). The folding of of newly synthesized proteins to mature forms is controlled by the "protein quality control" mechanism, which is tightly regulated in the ER. The proteins that can not reach the final form due to mutations, genotoxic effects or cellular stress are firstly incorporated into the repetitive folding process in order to prevent arrival to their functional site. Nonetheless, proteins that can not fold properly, are transported to 26S proteasome for degradation via recognition and ubiqitination by a mechanism known as as ER-associated protein degradation (ERAD) pathway. It is also known that ERAD regulates endogenous levels of many normal proteins under physiological conditions. Many key molecules such as channel proteins, chaperones, E1-E2-E3 enzymes involved in ubiquitination, motor proteins responsible for retrotranscription, and cofactors accompanying the process are in sync with each other In ERAD. It is known that ubiquitin ligases and their dynamic ERAD complexes, unfolded protein response (UPR) and endogenous ERAD inhibitor protein play a role in the regulation of ERAD. The ERAD inhibitor protein SVIP expression has been reported to decrease after androgen administration in a LONG-SAGE library screening examined the androgen-mediated changes in gene expression, however no detailed information on regulation has been reported. From this, we hypothesized that ERAD could be regulated by androgens and aimed to examine ERAD-mediated regulation of androgens in our project. Within this PhD thesis, the regulation of ERAD through androgens was characterized and it was determined that the regulation of ERAD is mediated by direct regulation of the androgen receptor (AR). It is known that AR signalization plays an important role in the development of prostate cancer. The roles of ERAD members in prostate cancer cells were examined by functional tests. ERAD has been shown to have an important role in regulation of proliferative, migratory and malignant transformation abilities of prostate cancer cells. The data, we have revealed, suggests that ERAD may be a mechanism to be targeted in the development of prostate cancer and in the treatment of prostate cancer. In conclusion, the results of our project will shed light on both literature and the formation of new projects and also the design of potential therapeutic approaches.
Açıklama
Anahtar Kelimeler
ERAD, Androjen, Prostat kanseri, LNCaP, Androgen, Prostate Cancer, LNCa
