Presentation

Equipe de Recherche Fondamentale  "Oncogenèse et réponse au stress"


Dr Dmitry BULAVIN, DR1 INSERM, Chef d'Equipe


Résumé


Understanding the mechanisms underlying the behavior of stem cells and their implications in tumorigenesis and ageing are of great importance and paramount to the design of more effective treatments for human diseases. In many, if not all instances, in vivo interrogation of stem cells is linked to the lineage tracing protocols, which, in turn, depends on the identification of appropriate stem cell markers. We recently identified several such markers, including Wip1 phosphatase. Wip1 phosphatase is a member of PP2C family of phosphatases and is highly abundant in neural progenitors and intestinal stem cells. Functionally, Wip1 is a negative regulator of p38 MAPK and ATM-dependent signaling pathways, both of which play critical roles in regulating tumorigenesis and ageing. Using our recently developped tools and acquired knowledge, we emphasize the role of stem cells in regulation of tumorigenesis and ageing with particular interest in stress and DNA damage signaling kinases p38 MAPK and ATM as well as phosphatases, Wip1 and PP2A.

Projet de Recherche

Projet de Recherche


Role of DNA damage and stress-induced signaling in cancer



WIP1, a serine/threonine phosphatase encoded by the PPM1D gene, is overexpressed, amplified and mutated in several types of cancer including those of the mammary gland and colon. WIP1 plays a critical role in accelerating tumorigenesis by inactivating p53 and INK4a/ARF tumor suppressor pathways. In addition, WIP1 is involved in cancer progression through regulation of several DNA repair pathways including base excision repair (BER) as well as those controlled by ATM. WIP1 played a critical role in modulating DNA methylation patterns but also orchestrated the targeting of Activation-Induced cytidine Deaminase (AID) to CG-reach sequences. AID is a central enzyme for both class switch recombination and formation of somatic hypermutations. AID generates U:G mismatch that may trigger A/T and C/G pair mutations if not correctly repaired by BER. In turn, WIP1 overexpression resulted in increased H3K4me3 at CG-reach regions creating a platform for AID recruitment that could potentially facilitate the generation of an U:G mismatch. Since WIP1 also blocks BER pathway activity, this mismatch may not be properly repaired thus increasing the mutation frequency.

An accumulation of mutations and genomic instability play detrimental roles in cancer progression however the molecular mechanisms explaining their appearance are not fully understood. This raised the question as to whether WIP1-dependent modulation of CG-rich sequences and enhanced recruitment of AID could play a role in tumorigenesis. By analyzing somatic mutation datasets for human breast cancers we found a strong positive correlation between the occurrence of C-to-T transitions and total mutation load with both WIP1 copy numbers and WIP1 expression levels. It is important to understand whether other genetic alterations including deletions, insertions, duplications and chromosome translocations are regulated through WIP1-BRCA1-AID pathway. Despite several remaining questions, our initial analysis suggests the ability of WIP1 to de-repress heterochromatin-associated sequences including retroelements. Thus, WIP1 overexpression in human cancers could be one of the mechanisms contributing to genomic instability and cancer evolution.

Figur Legend :

Declining of Wip1 levels (shown in green) in sub-ventricular zone (SVZ) in mice with age.
Mice of different age (2-10 months) are shown.

Stress signaling in aging

In parallel with our efforts to understand the role of Wip1 in tumorigenesis, we investigate the molecular basis of ageing (Figure). The process of organismal ageing is characterized by the functional decline and diminished capacity of different tissues to respond to injury or stress. As stem cells are involved in homeostasis as well as the regeneration and repair of many tissues, the question naturally arises as to whether ageing tissue is characterized by a decline in functional competence of resident adult stem cells. These questions will be approached first by the use of mouse strains with different levels of expression of Wip1 and p38 MAPK. 
 

Equipe de Recherche

Equipe de Recherche





2016


BULAVIN Dmitry, DR1 INSERM, Chef d'équipe

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BAILLEUX Caroline, Master 2 INSERM

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EMELYANOV Alexander, CDD CR INSERM

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FILIPPONI Doria, CDD CR INSERM

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GROSSE Laurent, Post Doc INSERM

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Presse & Media

Nice-Matin, 17 Juin 2017




Extrait du site de la Fondation ARC, Décembre 2016




Publications

2017


Brichkina A, Bulavin DV.

Cancer suppression by systemic inactivation of p38MAPK.

Oncotarget. 2017, Feb 11.


Brichkina A, Bertero T, Loh HM, Nguyen NT, Emelyanov A, Rigade S, Ilie M, Hofman P, Gaggioli C, Bulavin DV.

p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis.

Genes Dev. 2016 Dec 1;30(23):2623-2636.


Cortez I, Bulavin DV, Wu P, McGrath EL, Cunningham KA, Wakamiya M, Papaconstantinou J, Dineley KT.

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning.

Behav Brain Res. 2017 Mar 30;322(Pt B):212-222.


2016


Authors ……   Bulavin DV, …….

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).

Autophagy, 2016, Jan2;12(1):1-222.



2015


Papaconstantinou J, Wang CZ, Zhang M, Yang S, Deford J, Bulavin DV, Ansari NH.

Attenuation of p38α MAPK stress response signaling delays the in vivo aging of skeletal muscle

myofibers and progenitor cells.

Aging (Albany NY), 2015, Sep;7(9):718-33.


2014


Huang YF, Bulavin DV.

Oncogene-mediated regulation of p53 ISGylation and functions.

Oncotarget., 2014, Jul 30;5(14):5808-18.


Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin DV.

Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging.

J. Clin. Invest., 2014, Jul 1;124(7):3263-73.


Huang YF, Wee S, Gunaratne J, Lane DP, Bulavin DV.

Isg15 controls p53 stability and functions.

Cell Cycle, 2014, Jul 15;13(14):2200-10.



2013


Filipponi D, Bulavin D.

Wip1 and ATM in tumor evolution: role for BRCA1.

Oncotarget., 2013, Dec;4(12):2170.


Filipponi D, Muller J, Emelyanov A, Bulavin DV.

Wip1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation.

Cancer Cell, 2013, Oct 14;24(4):528-41.


Dudgeon C, Shreeram S, Tanoue K, Mazur SJ, Sayadi A, Robinson RC, Appella E,

Bulavin DV.

Genetic variants and mutations of PPM1D control the response to DNA damage.

Cell. Cycle, 2013, Aug 15;12(16):2656-64.


Zhu Y, Huang YF, Kek C, Bulavin DV.

Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations.

Cell. Stem Cell., 2013, Mar 7;12(3):298-303.


Tarulli GA, De Silva D, Ho V, Kunasegaran K, Ghosh K, Tan BC, Bulavin DV,

Pietersen AM.

Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium.

Breast Cancer Res., 2013, Jan 31;15(1):R10.



2012


Fernandez F, Soon I, Li Z, Kuan TC, Min DH, Wong ES, Demidov ON, Paterson MC,

Dawe G, Bulavin DV, Xiao ZC.

Wip1 phosphatase positively modulates dendritic spine morphology and memory processes through the p38MAPK signaling pathway.

Cell. Adh. Migr., 2012, Jul-Aug;6(4):333-43.


Brichkina A, Bulavin DV.

WIP-ing out atherosclerosis with autophagy.

Autophagy, 2012, Oct;8(10):1545-7.


Le Guezennec X, Brichkina A, Huang YF, Kostromina E, Han W, Bulavin DV.

Wip1-dependent regulation of autophagy, obesity, and atherosclerosis.

Cell. Metab., 2012, Jul 3;16(1):68-80.


Zhu YH, Bulavin DV.

Wip1-dependent signaling pathways in health and diseases.

Prog. Mol. Biol. Transl. Sci., 2012;106:307-25.


Goloudina AR, Tanoue K, Hammann A, Fourmaux E, Le Guezennec X, Bulavin DV,

Mazur SJ, Appella E, Garrido C, Demidov ON.

Wip1 promotes RUNX2-dependent apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents.

Proc. Natl. Acad. Sci USA, 2012, Jan 10;109(2):E68-75.



2010


Cha H, Lowe JM, Li H, Lee JS, Belova GI, Bulavin DV, Fornace AJ Jr.

Wip1 directly dephosphorylates gamma-H2AX and attenuates the DNA damage response.

Cancer Res., 2010, May 15;70(10):4112-22.


Le Guezennec X, Bulavin DV.

WIP1 phosphatase at the crossroads of cancer and aging.

Trends Biochem. Sci., 2010, Feb;35(2):109-14.


 

Huang YF, Bulavin DV.

Oncogene-mediated regulation of p53 ISGylation and functions.
Oncotarget, 2014, Jul 30;5(14):5808-18.


Filipponi D, Muller J, Emelyanov A, Bulavin DV. 

Wip1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation.

Cancer Cell., 2013, 24(4):528-541.





Zhu Y, Huang YF, Kek C, Bulavin DV. 

Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations.

Cell. Stem Cell, 2013, 12(3): 298-303.


Le Guezennec X, Brichkina A, Huang YF, Kostromina A, Han W, Bulavin DV. 

Wip1-dependent regulation of autophagy, obesity and atherosclerosis.


Cell. Metabolism, 2012, 16(1):68-80.


Wong ESM, Le Guezennec X, Demidov ON, Marshall NT, Wang ST, Krishnamurthy J, Sharpless NE, Dunn NR, Bulavin DV. 

p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. 


Dev. Cell., 2009, 17(1):142-9.


Demidov ON, Timofeev O, Lwin H, Kek C, Appella E, Bulavin DV. 

Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine.

Cell. Stem Cell, 2007, 1:180-190.


(Fev 2016)