Otofaji ve sinyal yolakları (Autophagy and signaling pathways)

Programlı hücre ölümü fizyolojik ve evrimsel olarak korunmuş bir süreç olup, özellikle çok hücreli organizmalarda embryolojik gelişim, doku sağlığı ve patojenlere karşı savunma gibi birçok yaşamsal olayda önemlidir. 1972 de yayınladıkları makalede, Kerr, Wyllie ve Currie, iki hücre ölümü türünden bahsederler; apoptoz, genetik olarak kontrol edilen programlı hücre ölümü ve nekroz, programlanmamış ve kazara olan hücre ölümü (Kerr et al. 1972). Takip eden 30 yılda, “apoptoz” terimi programlı hücre ölümünü tanımlamak için genel terim olarak kullanılıp, oluşumunun ardındaki moleküler mekanizma konusunda çok miktarda bilgi toplanmıştır. Apoptoz ve nekroz kavramlarının biyoloji camiasında yarattığı heyecan nedeniyle öne çıkması, apoptotik olmayan alternatif hücre ölüm mekanizmalarının varlığının bilim dünyasının büyük bölümü tarafından göz ardı edilmesine neden olmuştur. Son yıllarda, moleküler biyoloji alanında bilgi dağarcığının giderek genişlemesi ve apoptoz araştırmalarının artık bir doygunluğa ulaşması nedeniyle, alternatif programlı hücre ölüm yollarına olan ilgi artmıştır. Alternatif programlı hücre ölüm mekanizmalarından biri olan otofajik hücre ölümüne ilgi, maya otofaji genlerinin memeli karşılıklarının bulunması ve çalışmaların morfolojik tanımlardan moleküler düzeye inmeye başlaması sayesinde artmış, sonuç olarak, otofaji, apoptoza ek veya alternatif olarak düşünülen temel yollardan birisi haline gelmiştir. Bu makalede, otofaji ve otofajik hücre ölümünün morfolojik ve moleküler temelleri ve, apoptotik yolaklarla ilişkisi tanımlanacaktır. Bu konudaki temel problemlerden biri otofajinin katabolik ve yaşamsal rolleri ile hücre ölümündeki özelliklerini bir araya getirmektir. Bu yazıda bu konu son gelişmeler ışığında anlatılacaktır

Otofaji analiz yöntemleri ve uygulama aşamaları (Autophagy analysis techniques and applications)

Hücresel anlamda stres, hücrelerin işleyişini etkilemekte, doğal dengelerini bozmakta ve hatta ölümlerine neden olabilmektedir. Hücre düzeyinde maruz kalınan stres, doku ve organların işlevlerini aksatmalarına neden olabilmekte ve organizma genelinde kendisini hastalık olarak göstermektedir. Stres iç ve dış faktörlere bağlı olarak gelişebilir. Kronik hastalıkların metabolizma üzerinde etkileri, hormonal değişiklikler, biyokimyasal değişiklikler ya da uzun süreli enflamasyon iç faktörlere bağlı stresin nedenleri arasındadır. Besin, büyüme faktörü ya da oksijen eksikliği (iskemi), toksik maddeler, bazı ilaç ve kimyasallara maruz kalma, ultraviyole ışınları, radyasyon gibi ışımalar hücresel strese yol açabilen dış faktörler olarak sayılabilir. Ayrıca bazı kalıtsal hastalıklar (örneğin, kistik fibroz, alfa1-antitiripsin eksikliği vb) ya da kalıtsal komponenti olan hastalıklar (örneğin, Alzheimer ya da Parkinson hastalığı), hücre içinde ve dışında toksik etkiler gösteren anormal proteinlerin birikimine neden olarak hücresel strese yol açabilirler. Stresin nedenine göre farklı hücresel yolakların aktive olabilmesine karşın, yukarıda bahsedilenler dahil pek çok stres faktörüne karşı hücrelerin verdiği en temel iki yanıt otofaji ve stresin dozuna göre programlı hücre ölümüdür. Otofajik hücre ölümüne stres dışında, doku ve organ gelişimi sırasında da rastlamak mümkündür. Klasik olarak hücre ölümü apoptoz (programlı) ve nekroz (programsız) olarak iki sınıfa ayrılmıştı. Fakat son yıllarda yapılan çalışmalar, apoptoz dışı programlı hücre ölüm yolakları da bulunduğunu ortaya çıkarmıştır. Hatta “programlı nekroz” adı verilen hücre ölüm tiplerinin de bulunduğu önerilmiştir. Çoğunlukla bir stres yanıtı ve hayatta kalma mekanizması olarak işleyen otofajinin bile, özellikle apoptozun mümkün olmadığı durumlarda “otofajik hücre ölümü” adı verilen bir programlı hücre ölüm mekanizmasına dönüştüğü gözlenmiştir (Gozuacik D, 2007, Öz-Arslan D, 2011). Bu makalede otofajik hücre ölümü analiz yöntemleri tartışılacaktır

Techniques to Study Autophagy in Plants

Autophagy (or self eating), a cellular recycling mechanism, became the center of interest and subject of intensive research in recent years. Development of new molecular techniques allowed the study of this biological phenomenon in various model organisms ranging from yeast to plants and mammals. Accumulating data provide evidence that autophagy is involved in a spectrum of biological mechanisms including plant growth, development, response to stress, and defense against pathogens. In this review, we briefly summarize general and plant-related autophagy studies, and explain techniques commonly used to study autophagy. We also try to extrapolate how autophagy techniques used in other organisms may be adapted to plant studies

Autophagy: nobel prize and new results

In our lab in Sabanci University, Istanbul, we focus on signaling events regulating mammalian autophagy in health and disease. To discover new autophagy regulators and coordinators, we performed several unbiased functional screens. Our microRNA (miRNA) screens led to the discovery of several miRNAs targeting autophagy at various steps of the pathway. miRNAs are able to affect the expression of a number of proteins at once. Therefore, miRNA networks seem to integrate cellular stress response pathways including autophagy and apoptosis, and coordinate them to shape cell faith. Our published and unpublished results allowed us to have a better picture of the miRNA networks modulating autophagic responses in human health and disease. Protein interaction screens performed in our lab led us to discover novel proteins involved in auto-phagy regulation. In fact, some of these proteins were directly interacting with the core autophagy machinery components. Unexpected direct links between autophagy and other important cellular pathways were found, allowing us to reveal novel entry points for autophagy regulation and coordination in cells. Interestingly, some of this interactions seemed to be autophagy signal specific, and our work revealed novel dynamics in autophagy regulation. Results from our recently published and unpublished studies will be presented and physiological and pathological implications of our results will be discussed. *This work was supported by The Scientific and Technological Research Council of Turkey (TUBITAK) 1001 Grant number: 114Z982 and Sabanci University

Autophagy in health and disease

In our lab in Sabanci University, Istanbul, we focus on signaling events regulating mammalian autophagy in health and disease. To discover new autophagy regulators and coordinators, we performed several unbiased functional screens. Our microRNA (miRNA) screens led to the discovery of several miRNAs targeting autophagy at various steps of the pathway. miRNAs are able to affect the expression of a number of proteins at once. Therefore, miRNA networks seem to integrate cellular stress response pathways including autophagy and apoptosis, and coordinate them to shape cell faith. Our published and unpublished results allowed us to have a better picture of the miRNA networks modulating autophagic responses in human health and disease. Protein interaction screens performed in our lab led us to discover novel proteins involved in autophagy regulation. In fact, some of these proteins were directly interacting with the core autophagy machinery components. Unexpected direct links between autophagy and other important cellular pathways were found, allowing us to reveal novel entry points for autophagy regulation and coordination in cells. Interestingly, some of this interactions seemed to be autophagy signal specific, and our work revealed novel dynamics in autophagy regulation. Results from our recently published and unpublished studies will be presented and physiological and pathological implications of our results will be discussed.*This work was supported by The Scientific and Technological Research Council of Turkey (TUBITAK) 1001 Grant number: 114Z982 and Sabanci University

Novel ATG5 interactors in the control of basic autophagy and mitophagy

In our lab in Sabanci University, Istanbul, we focus on signaling events regulating mammalian autophagy in health and disease. To discover new autophagy regulators and coordinators, we performed several unbiased functional screens. Our microRNA (miRNA) screens led to the discovery of several miRNAs targeting autophagy at various steps of the pathway. miRNAs are able to affect the expression of a number of proteins at once. Therefore, miRNA networks seem to integrate cellular stress response pathways including autophagy and apoptosis, and coordinate them to shape cell faith. Our published and unpublished results allowed us to have a better picture of the miRNA networks modulating autophagic responses in human health and disease. Protein interaction screens performed in our lab led us to discover novel proteins involved in autophagy regulation. In fact, some of these proteins were directly interacting with the core autophagy machinery components. Unexpected direct links between autophagy and other important cellular pathways were found, allowing us to reveal novel entry points for autophagy regulation and coordination in cells. Interestingly, some of this interactions seemed to be autophagy signal specific, and our work revealed novel dynamics in autophagy regulation. Results from our recently published and unpublished studies will be presented and implications of our results in human health problems, including cancer and degenerative diseases, will be discussed. *This work was supported by grant numbers 110T405 and 114Z982 of The Scientific and Technological Research Council of Turkey, TUBITAK (legally bound to declare the grant numbers)

Autophagy: a cellular stres and a cell death mechanism (Otofaji: bir hücresel stres yanıtı ve ölüm mekanizması)

Autophagy is a physiological phenomenon responsible for the degradation of long-lived proteins, organelles and cytoplasmic fragments. It allows cellular recycling following lysosomal degradation and helps the cell to survive various stress conditions including starvation, growth factor and oxidative stress. Paradoxically, under certain conditions autophagy may kill the cell through a caspase-independent, non-apoptotic type of cell death (Type II cell death or autophagic cell death). Several lines of evidence point out to a direct connection between classical apoptosis and autophagy. Molecular mechanisms of apoptosis-autophagy connection start to be unraveled. The cross-talk between autophagy and apoptosis seems quite complex but certainly is critical for the development of novel diagnosis, follow-up and treatment modalities in health problems such as cancer, infections and neurodegenerative diseases

Autophagy and cancer

Autophagy is an evolutionary conserved intracellular degradation and stress response mechanism that is mainly responsible for the breakdown and recycling of cytoplasmic materials, including long-lived proteins, protein aggregates, and damaged organelles. In this way, autophagy provides the cell with building blocks and allows the maintenance of homeostasis under stress conditions such as growth factor deficiency, nutrient deprivation, hypoxia, and toxins. Consequently, abnormalities of autophagy contribute to a number of pathologies ranging from neurodegenerative diseases to cancer. Autophagy was reported to have a dual role in cancer. Depending on cancer stage, autophagy seems to act as tumor suppressor or as a mechanism supporting tumor growth and spread. In this review, we provide a summary of the relevant literature and discuss the role of autophagy in cancer formation and chemotherapy responses

Autophagy and liver cancer

Autophagy is a key biological phenomenon conserved from yeast to mammals. Under basal conditions, activation of autophagy leads to the protein degradation as well as damaged organelles for maintaining cellular homeostasis. Deregulation of autophagy has been identified as a key mechanism contributing to the pathogenesis and progression of several liver diseases, including hepatocellular carcinoma (HCC), one of the most common and mortal types of cancer. Currently used treatment strategies in patients with HCC result in variable success rates. Therefore, novel early diagnosis and treatment techniques should be developed. Manipulation of autophagy may improve responses of cancer cell to treatments and provide novel targeted therapy options for HCC. In this review, we summarized how our understanding of autophagy-cell death connection may have an impact on HCC therapy