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The role of centrosome in eukaryotic cell architecture: redox regulation of TBCCD1 network

Faculdade de Ciências da Universidade de Lisboa
Project classification

Scientific area

1.6 Biological sciences (Medical sciences go to scientific area 3.n; Agricultural sciences go to scientific area 4.n)

Discipline(s)

Biochemistry and molecular biology
Cell biology, Microbiology

Project description

Project title

The role of centrosome in eukaryotic cell architecture: redox regulation of TBCCD1 network

Scientific Coordinator's name:

Helena Soares & Susana Marinho

Scientific Coordinator's e-mail:

mhsoares@fc.ul.pt

Principal R&D Unit:

Centro de Química e Bioquímica (CQB)

Other R&D Units involved in the project:

Other R&D units involved in the project

Project keyword(s)

centrosome, nucleus, cilia, ciliopathies, intrinsic-polarity, TBCCD1 partners, redox regulation, Hydrogen peroxide

Short abstract and comments

Published work from our group identified a new TBCC domain-containing human protein (TBCCD1) and showed that it is a centrosomal component that also localizes to the spindle midzone, midbody and basal bodies/transition zone of primary and motile cilia. TBCCD1 silencing in RPE-1 cells causes a marked increase in the centrosome-nucleus distance, a cell cycle delay, GA disorganization and lower efficiency to assemble primary cilia. Moreover, silenced cells were larger and slower than control cells and in wound healing assays were able to close the wound but were delayed showing collective cell migration alterations. By performing mutational analysis we already identified the minimum domain required to localize TBCCD1 at the centrosome. We have already established the interactome of TBCCD1 that shows that the protein interacts with a vast number of proteins that are related to cilia assembly, centrosome function and microtubule dynamics. Striking some of these proteins are potentially regulated by hydrogen peroxide (H2O2), a hypothesis that we are exploring. Our results implicate TBCCD1 in cell polarity, cell migration and primary cilia assembly/function, and consequently it might play critical roles during vertebrate development. Therefore, our main goal is to identify the molecular mechanisms and pathways in which TBCCD1 is involved and if they are redox regulated.

Potential uses/indications

Our results indicate that TBCCD1 protein plays a critical role in the centrosome-nucleus connection and therefore affects ciliogenesis, cell division and migration. Therefore, our studies have the potential to reveal a new protein and pathway playing a critical role in human diseases involving cilia dysfunction generally known as ciliopathies. Over a dozen disorders are now considered to be within the ciliopathy spectrum including Joubert syndrome (JBTS), nephronophthisis (NPHP), Senior-Loken syndrome (SLS), orofaciodigital (OFD), Jeune syndrome, autosomal dominant and recessive polycystic kidney disease (ADPKD and ARPKD), Leber congenital amaurosis (LCA), Meckel-Gruber syndrome (MKS), Bardet-Biedl syndrome (BBS), Usher syndrome (US) and some forms of retinal dystrophy (RD). Between them, these conditions involve nearly every major body organ including kidney, brain, limb, retina, liver, and bone, highlighting the important role of the primary cilium in development and homeostasis. Moreover, in patient cells of X-linked Emery–Dreifuss muscular dystrophy the centrosome is mislocated at the periphery of the cells similar to what is observed in cells depleted of TBCCD1. These individuals display a mutation in emerin gene that encodes a nuclear membrane protein, and the muscular disease is characterized by slowly progressive skeletal muscles, major tendons, and the cardiac conduction system weakness and wasting. As TBCCD1 is a conceivable key regulator of centrosome positioning and consequently of internal cell organization, this protein has the potential to play a critical role both in myoblasts cell architecture and migration which are required for muscle development. Moreover, the fact that primary cilia signaling seems to play an important role in early differentiation of muscle cells and TBCCD1 is required to normal cilia biogenesis also supports our hypothesis.

Status

Ongoing

Partner Status: Seeking Partners?

Yes

Grant number (QREN, FP7, Eureka, etc)

UID/Multi/00612/2013 given to CQB & IDI&CATBCCentro -IPL– 016

Last edited on

2017-02-13 11:31:46

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