RESEARCH FOCUS

KEYWORDS: Cancer biology, mammalian signaling pathways, cellular stress, programmed cell death, apoptosis and autophagy, disease biology, drug research, molecular and nano medicine, stress and death mechanisms in nanotoxicology and tissue engineering.

AUTOPHAGY IN HEALTH AND DISEASE:

Gozuacik lab’s research theme is cellular stress and death responses (see Gozuacik D, Curr. Top. in Devel. Biol, 2007. PDF Version). In particular, we focus on autophagy regulation in mammals, autophagy-cell death and autophagy-apoptosis connection, autophagy-UPS connection and autophagy abnormalities in human diseases.

Overview:

Cells are equipped with various molecular mechanisms to cope with stress imposed by changing environmental conditions. One of these stress response mechanisms is called autophagy. It is characterized by sequestration of bulk cytoplasm and organelles in double or multimembrane autophagic vesicles, and their delivery to and subsequent degradation by the cell’s own lysosomal system (Figure 1; also see Gozuacik D, Oncogene, 2004. PDF version). So, the cell eats itself from inside in response to stress, allowing it to recycle its building blocks (i.e. aminoacids) and survive the unfavourable conditions. Causes of stress are variable and include nutrient and growth factor deprivation, reactive oxygen accumulation and toxins (Figure 2).

Fig. 1. Stages of autophagic vesicle formation and autophagic degradation.

Fig. 2. Activation of autophagy (green dots) by stress. Starvation or chemicals (ER stress inducers Thapsigargin or Tunicamycin) stimulate autophagy in GFP-LC3 (a fluorescent autophagy marker) transgenic cells.

Autophagy in cell survival and death:

 Autophagy also functions at a basal level under physiological conditions. This activity contributes to the maintenance of cellular homeostasis by regulating the turnover of long-lived or aggregated proteins and damaged organelles (Figure 3). Therefore, autophagy may function as a survival mechanism under various cellular and organismal settings. Yet, depending on the character and the duration of stress, autophagy may contribute to cellular demise as well. Autophagic activity is considered as the hallmark of an alternative, caspase-independent form of programmed cell death, named autophagic type II cell death. Moreover, autophagy and apoptosis seem to be interconnected positively or negatively, introducing the concept of “molecular switches” between them.

 

Fig. 3. Electron microscopic (TEM) picture of a double membrane autophagic vesicle (arrow) containing cytoplasm and a degenerating mitochondrion.

Autophagy and human disease:

We are just beginning to understand the connection between autophagy and human disease. Malignant transformation (cancer) is frequently associated with suppression of autophagy. While some cancer cells respond to anticancer treatments by autophagy activation, autophagic cell death induction was proposed as a cancer treatment modalitiy. Neurodegenerative diseases such as Huntington disease are aggravated by an accompanying defect in the clearance of abnormal-aggregated proteins by autophagy. Recent studies point out to the importance of autophagy in the pathologies of stroke and myocardial infarction. While autophagy serves as a line of defense against intracellular pathogens, some bacteria and viruses evolved to use it for their own benefit.

Our research approach:

In spite of its critical role in human health and disease, basic mammalian autophagy regulation pathways are ill-defined. Contribution of autophagy abnormalities to most human diseases are yet to be established. Autophagy manipulation has a big potential as a treatment approach but only a few drugs or drug targets were described so far. Moreover, pathways connecting autophagy to cell death and survival remain largely obscure. Therefore, our laboratory aims at contributing to the research efforts in this field. We use the tools of molecular biology, biochemistry, cell biology and genetics and, collaborate with clinicians and bioinformaticians to study autophagy in health and disease. Our close collaboration with the robotics (mechatronics), electronics, computer sciences and physics laboratories of our university help us to develop new biology-related tools for our research.

OUR NATIONAL AND INTERNATIONAL COLLABORATIONS:

Gozuacik Lab has privileged access to the EMBL Core Facilities. Sabanci University is in close vicinity of “GOSB Technopark” and Marmara Technopark (Teknokent), important science and technology parks in Turkey. Sabanci University research patents and outputs are commercialized with the help of its affiliated company Inovent. We work in close collaboration with research teams in Bogazici, Marmara, Maltepe, Yeditepe, Koc, Bilkent, METU, Ege, Dokuz Eylul and Istanbul Technical Universities, IYTE and GYTE Institutes (in Istanbul, Ankara and Izmir). Our collaborators include EMBO YIP Labs (All around Europe), Dr Reuven Agami (The Netherlands Cancer Institute), Dr Yoon Kyoung Cho (UNIST, S. Korea), Dr Ali Kosar (Sabanci University), Dr Bahattin Koc (Sabanci University), Dr Osman Ugur Sezerman (Sabanci University), Dr Sinan Ekici (Maltepe University), Dr Isin Dogan Ekici (Yeditepe University). Gozuacik Lab is part of the EMBO Cancer YIPs Group (15 labs all around EU) and Inproteolys European Network (more than 40 labs in EU).

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