The role of small GTPase Rac1 in stress signaling

Güngör Burçin
The role of small GTPase Rac1 in stress signaling.
PhD, University of Szeged.
(2014)

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Abstract in foreign language

The heat shock response, one of the most studied cellular homeostatic mechanisms, is involved in the maintenance of cell functionality during stress. Yet, the whole stress signaling pathway has not been elucidated. In line with the membrane thermosensor model, mild stress, or “membrane defects” caused by different disease states, is sensed by changes in the fluidity and microdomain structure of membranes, influencing membrane localized signaling activities. In favor of this model, our group exposed different mammalian cells to various membrane fluidizers or drugs with the ability to interact with certain membrane lipids and found substantial modulation of heat shock protein (HSP) expression. One possible signaling pathway originating from plasma membrane involves the lipid kinase, PI3kinase, which in turn activates the small GTPase, Rac1. Through downstream signaling cascade to MAP kinases, the main transcription factor, HSF1 is activated leading to HSP synthesis. It was shown that Rac1 translocation to the plasma membrane is essential for activating downstream effectors and its membrane binding is determined at least in part by membrane lipids. In favor of “membrane stress sensor” model, our working hypothesis was that Rac1 pathway is involved in stress signaling through the effect of stress on membrane microdomain organization. As a proof of concept, well established Rac1 specific inhibitor NSC23766 along with 2-bromopalmitate - which blocks Rac1 palmitoylation necessary to interact Rac1 with the liquid ordered membrane domains - have been investigated. We have shown that using specific Rac1 inhibitor, NSC23766 and 2-Brp, the heat shock response decreased remarkably in dose dependent manner. Moreover, elevated levels of heat shock response achieved by addition of HSP co-inducer, BGP15 is diminished by NSC23766. We showed, that palmitoylation affects Rac1 relocalization under stress conditions and, the p38 MAPK pathway has a key role in the Rac1 actions, described. Not only the relocalization of Rac1 to the plasma membrane but also its capacity for microdomain remodeling have been documented. Besides, cytoskeletal changes upon heat treatments and inhibitor administrations have been shown by taken SEM photos. Data gained above are further confirmed by the generation of stable clones with palmitoylation deficient, constitutively active and dominant negative Rac1 mutations. As a conclusion, Rac1 is a major mediator of heat stress signal transduction between plasma membrane and prominent HSP genes tested, in melanoma cells. This small GTPase is directly involved in the modulation of HSP expression through controlling the stress induced remodeling of membrane microdomains.

Item Type: Thesis (PhD)
Creators: Güngör Burçin
Hungarian title label: The role of small GTPase Rac1 in stress signaling
Title of the thesis in foreign language: The role of small GTPase Rac1 in stress signaling
Divisions: Doctoral School of Biology
Discipline label: természettudományok > biológiai tudományok
Defence date label: 2014. June 30.
Supervisor label:
SupervisorSupervisor scientific name labelEmail
Dr. Horváth IbolyaPhD, tudományos főmunkatárs, MTA SZBK Biokémiai Intézethibi@brc.hu
Reviewer label:
Reviewer name labelReviewer scientific name labelEmail
Dr. Veres Balázsegyetemi docens, Ph.D., PTE ÁOK Biokémiai és Orvosi Kémiai IntézetBalazs.Veres@aok.pte.hu
Dr. Csonka Csabatudományos főmunkatárs, Ph.D., SZTE ÁOK Biokémiai Intézet csaba@biochem.szote.u-szeged.hu
President label:
President name labelPresident scientific name labelEmail
Dr. Fekete Évaprofessor emerita, az MTA doktora, SZTE TTIK Élettani, Szervezettani és Idegtudományi Tanszékefekete@bio.u-szeged.hu
Member label:
Member name labelMember scientific name labelEmail
Dr. Széll Mártatanszékvezető egyetemi tanár, az MTA doktora, SZTE ÁOK Orvosi Genetikai Intézetszell.marta@med.u-szeged.hu
Dr. Benyhe Sándortudományos tanácsadó, az MTA doktora, MTA SZBK Biokémiai Intézetbenyhe.sandor@brc.mta.hu
Item ID: 2239
doi: https://doi.org/10.14232/phd.2239
Date Deposited: 2014. Jun. 02. 12:34
Last Modified: 2015. Jan. 15. 12:32
Depository no.: B 5741
Supervisor: Dr. Horváth Ibolya
Supervisor scientific name label: PhD, tudományos főmunkatárs, MTA SZBK Biokémiai Intézet
URI: http://doktori.bibl.u-szeged.hu/id/eprint/2239
Defence/Citable status: Defended.

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