The role of small GTPase Rac1 in stress signaling
Başlık çevirisi mevcut değil.
- Tez No: 544376
- Danışmanlar: Dr. IBOLYA HORVáTH
- Tez Türü: Doktora
- Konular: Biyoloji, Biology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2014
- Dil: İngilizce
- Üniversite: University of Szeged
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 99
Özet
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Özet (Çeviri)
All organisms are exposed to many external challenges now and then such as elevated temperatures, oxidative stress, UV irradiation and hypoxia resulting in protein denaturation and DNA damage. Not only environmental conditions but also pathophysiological states - such as neurodegenerative diseases, diabetes and cancer - can act as stress factors. Most of these insults are also reported to target membranes and lipids. Exposure of cells to a transient, non-lethal stress results in the activation of cellular stress responses and induces a state of stress tolerance that renders them resistant to subsequent lethal insults. Thus, thermotolerant tumor cells are not only less sensitive to hyperthermia-induced cytotoxicity, but also for growth factor withdrawal, heavy metals, radiation or anticancer drugs. The state of thermotolerance is associated with the synthesis and cellular accumulation of a family of highly conserved proteins referred to as heat shock proteins (HSPs). HSPs are named according to their molecular weights: HSP100, HSP90, HSP70, HSP60 and the“small HSPs”. They can reside in different compartments of the cell and can also associate with membranes via their specific protein and lipid interactions. The most prominent HSPs, HSP70 and HSP27 contribute to stress- and thermotolerance mainly through their molecular chaperone activity. There is a growing body of evidence linking the HSP expression induced by a variety of stress conditions to changes in the lipid composition and in the architecture of membranes. The“membrane thermosensor”hypothesis postulates that besides protein denaturation or alteration in nucleic acid conformation, heat stress can be sensed through subtle changes in the fluidity and micro-domain hyperstructures of membranes influencing the operation of membrane-localized stress sensing and signaling apparatuses and hence, the expression of HSPs. Having more information about the structure, organization and function of plasma membrane (PM) has recently opened up new doors to understand its novel role as cellular stress sensor. Lipid micro-domains are the hyperstructures of cholesterol (Chol), sphingomyelin and saturated lipid containing liquid ordered (Lo) patches of PM. Specific signaling proteins are targeted to these micro-domains as a consequence of their lipidated features. The Rho family small GTPase Rac1 is an important integrator of signals from growth factor receptors, integrins and altered signaling related to cell transformation, tumor invasion, and metastasis. Rac1 is known to promote actin assembly and have an important role in the formation of lamellipodia and membrane ruffles. Rac1 associates with Chol rich PM micro-domains under growth factor stimuli. Rac1 is also known to drive actin polymerization which can be induced by mild hyperthermia. In favor of membrane thermosensor model, our current working hypothesizes was that Rac1 pathway is involved in stress signaling, especially through the effect of heat stress on membrane micro-domain organization. We assumed that plasma membrane rearrangement and/or hyperfluidization caused even by mild heat stress may activate growth factor receptor tyrosine kinases by their non-specific clustering. Activation of such cell surface receptors can stimulate PI3K which in turn activates the Rac1 protein, resulting in its release from its pre-existing Rho-GDI association keeping Rac1 solubilized in cytosol. Next we suggested, that Rac1, undergoing reversible palmitoylation subsequently translocates to the Chol rich domains of PM. Finally, this surface membrane localized Rac1 pool interacts with its effector Pak1, which mediates a downstream signaling cascade to MAPKs such as p38MAPK directly affecting HSP expression. In order to test our above described working hypothesis, first we have monitored the Rac1 PM localization, both under mild and severe heat stress conditions. By using the B16F10 mouse melanoma cells we have shown that not only its functionally active form but also the palmitoylation of Rac1 is a prerequisite for its PM localization. Next we evidenced, that exposure of cells to heat shock causes a distinct alteration of micro-domains of PM. We have shown that Rac1 palmitoylation can be one of the major regulatory steps for the observed increment of micro-domains in these cells pre-exposed to heat stress. Studying the heat shock effect on cell shape alterations, our findings have indicated that severe thermal treatments result in cell shrinkage and rounding in B16F10 melanoma. Using an additional cellular model system, we have demonstrated the F-actin fragmentation under severe heat stress in MEF cells. We also documented, that this effect can be prevented by administration of Rac1 specific and palmitoylation inhibitors. In order to test the effect of Rac1 on HSP expression, next we have analyzed the expressions of inducible hsp25 and hsp70 genes under both mild and severe heat shock conditions. Our results have revealed that, activation of Rac1 influences the expression of hsp25 and hsp70 at both mRNA and protein levels under mild heat stress conditions which also triggers PM Rac1 localization on the Lo micro-domains. The hydroximic acid derivative, BGP15 is a well-studied HSP co-inducer and was also shown to interact with membranes. We have reported that BGP15 acts as a raft stabilizer for the integrity of lipid nano-platforms. We have shown that Rac1 can also regulate the BGP15-mediated activation of HSPs. Finally, we have documented that blocking Rac1 function by its specific inhibitor NSC under mild heat shock conditions is causing elevated phosphorylation levels of p38MAPK which is known to phosphorylate the major transactivator HSF1 on its inhibitory side to attenuate HSP expression. Although our efforts to test HSF1 hyperphosphorylation displayed no measurable changes on the overall phosphorylation pattern of HSF1, obviously further investigations are needed to elucidate whether the documented Rac1 linked activation of HSPs is HSF1-mediated or not.
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