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Présentation

Basic Research Team  "Telomerase and adult stem cell homeostasis "


Marina SHKRELI, CR1 INSERM, Chef d'Equipe


Summary


Telomeres are nucleoprotein complexes that protect the ends of eukaryotic chromosomes. Maintenance of the G-rich repeat DNA sequences constituting telomeres is mediated by telomerase – a ribonucleoprotein complex that acts as a reverse transcriptase. The minimal telomerase holoenzyme consist of TERT, the telomerase reverse transcriptase catalytic subunit, and TERC, the telomerase RNA subunit encoding the template sequence that is reverse transcribed by the telomerase enzyme to telomeres.

Non-telomeric activity of telomerase on tissue homeostasis
Beside its well-established role in telomere synthesis, there is evidence that telomerase exhibits other activities that are important in cancer and in normal stem/progenitor cells. Several studies have indeed shown that telomerase possess a telomere-lengthening independent role in promoting epithelial cancer and in blocking apoptosis, and TERT was found to directly activate quiescent hair follicle stem cell. In addition, we found that transgenic TERT expression in mice induces proliferation and loss of differentiation markers of kidney epithelial cells named podocytes. The ability of TERT to activate podocytes is independent of TERC and of catalytic function, and is associated to a marked up-regulation of Wnt signaling. Moreover, we found that TERT-induced podocyte activation is reversible after TERT withdrawal, as differentiated podocytes reappear in the kidney (Figure). These data reveal an unexpected property of podocytes to reversibly enter cell cycle, suggest that podocyte renewal is an important feature of glomerular homeostasis and implicate the telomerase and Wnt signaling in podocyte renewal and disease.

 - kidney glomeruli -

Research Project

Research Project


To study kidney homeostasis, regeneration and aging

We found that TERT causes a dramatic effect on kidney podocytes, resulting in acute cell cycle entry and loss of differentiation markers. These observations have led us to hypothesize that podocytes in fact possess significant regenerative capacity, a potential revealed by activation of a telomerase signaling pathway. We are therefore investigating the cellular and molecular mechanisms involved in podocytes renewal by the mean of genetic approaches in vivo, and we aim to determine if podocyte renewal capacity is impaired during organismal aging.



To study the role of telomerase non-canonical activity in cancer development

The ability of telomerase to maintain and stabilize telomeres was clearly shown to be critical in mediating the ability of cancer cells to proliferate in an immortal fashion. In addition, recent observations suggest that the ability of telomerase to support proliferation and tumorigenesis extends beyond its activity in preventing critical telomere shortening. However, the precise impact of TERT’s ability to modulate Wnt signaling on tumorigenesis and cancer progression in vivo remains unknown. We are therefore investigating the impact of TERT activity, which is independent of telomere elongation, on tumorigenesis and cancer progression in vivo.

 

Research Team

Research Team



photo 2017

From left to right : Marina Shkreli, Lou Duret, Catherine Pons, Margo Montandon, Ségolène Maire



SHKRELI Marina, CR1 INSERM, Team Leader
Tel.: +33 (0)4 93 37 76 38, E-mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it

DURET Lou, Master 2 Student

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MAIRE Ségolène, IUT Trainee

Tel.: +33 (0)4 93 37 76 38, E-mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it


MONTANDON Margo, Graduate Student UNS

Tel.: +33 (0)4 93 37 76 38, E-mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it


PONS Catherine, TCE INSERM

Tel.: +33 (0)4 93 37 76 38, E-mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it

 


Laboratory : Tel.: +33 (0)4 93 37 76 83

(June 2017)



Publications

Publications


http://www.ncbi.nlm.nih.gov/pubmed/?term=marina+shkreli


2013


Diala I, Wagner N, Magdinier F, Shkreli M, Sirakov M, Bauwens S, Schluth-Bolard C, Simonet T,

Renault VM, Ye J, Djerbi A, Pineau P, Choi J, Artandi S, Dejean A, Plateroti M, Gilson E.

Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway.

EMBO Rep., 2013, Apr;14(4):356-63.


2011


Shkreli M, Sarin KY, Pech MF, Papeta N, Chang W, Brockman SA, Cheung P, Lee E, Kuhnert F,

Olson JL, Kuo CJ, Gharavi AG, D'Agati VD, Artandi SE.

Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase

and Wnt signaling.

Nat. Med., 2011, Dec 4;18(1):111-9.


Zhong F, Savage SA, Shkreli M, Giri N, Jessop L, Myers T, Chen R, Alter BP, Artandi SE.

Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita.

Genes Dev., 2011, Jan 1;25(1):11-6.


2010


Sacco A, Mourkioti F, Tran R, Choi J, Llewellyn M, Kraft P, Shkreli M, Delp S,

Pomerantz JH, Artandi SE, Blau HM.

Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice.

Cell, 2010, Dec 23;143(7):1059-71.


2009


Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H,

McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE. Telomerase modulates Wnt

signalling by association with target gene chromatin.

Nature, 2009, (460, 66-72).


2007


Shkreli M, Dambrine G, Soubieux D, Kut E, Rasschaert D.

Involvement of the oncoprotein c-Myc in viral telomerase RNA gene regulation during

Marek’s disease virus-induced lymphomagenesis.

Journal of Virology, 2007 (81, 4848-4857).


2003


Sadeyen JR, Tourne S, Shkreli M, Sizaret PY, Coursaget P.

Insertion of a foreign sequence on capsid surface loops of human papillomavirus type 16

virus-like particles reduces their capacity to induce neutralizing antibodies and delineates

a conformational neutralizing epitope.

Virology, 2003 (309, 32-40).



(Feb 2016)