28. Laurent-Matha, V., Lucas, A., Huttler, S., Sandhoff, K., Garcia, M., andRochefort, H. Procathepsin D interacts with prosaposin in cancer cells but itsinternalization is not mediated by LDL receptor-re<strong>la</strong>ted protein. Exp Cell Res,277: 210-219, 2002.29. Herz, J. The switch on the RAPper's neck<strong>la</strong>ce. Mol Cell, 23: 451-455, 2006.30. Dedieu, S., Langlois, B., Devy, J., Sid, B., Henri<strong>et</strong>, P., Sartel<strong>et</strong>, H., Bellon, G.,Emonard, H., and Martiny, L. LRP-1 silencing prevents malignant cell invasion<strong>de</strong>spite increased pericellu<strong>la</strong>r proteolytic activities. Mol Cell Biol, 28: 2980-2995, 2008.31. Song, H., Li, Y., Lee, J., Schwartz, A. L., and Bu, G. Low-<strong>de</strong>nsity lipoproteinreceptor-re<strong>la</strong>ted protein 1 promotes cancer cell migration and invasion byin<strong>du</strong>cing the expression of matrix m<strong>et</strong>alloproteinases 2 and 9. <strong>Cancer</strong> Res, 69:879-886, 2009.32. Benes, P., Jurajda, M., Zaloudik, J., Izakovicova-Hol<strong>la</strong>, L., and Vacha, J.C766T low-<strong>de</strong>nsity lipoprotein receptor-re<strong>la</strong>ted protein 1 (LRP1) genepolymorphism and susceptibility to breast cancer. Breast <strong>Cancer</strong> Res, 5: R77-81, 2003.33. Montel, V., Gaultier, A., Lester, R. D., Campana, W. M., and Gonias, S. L. Thelow-<strong>de</strong>nsity lipoprotein receptor-re<strong>la</strong>ted protein regu<strong>la</strong>tes cancer cell surviva<strong>la</strong>nd m<strong>et</strong>astasis <strong>de</strong>velopment. <strong>Cancer</strong> Res, 67: 9817-9824, 2007.34. Koong, A. C., Denko, N. C., Hudson, K. M., Schindler, C., Swiersz, L., Koch,C., Evans, S., Ibrahim, H., Le, Q. T., Terris, D. J., and Giaccia, A. J. Candidategenes for the hypoxic tumor phenotype. <strong>Cancer</strong> Res, 60: 883-887, 2000.21
35. Bando, H., Toi, M., Kitada, K., and Koike, M. Genes commonly upregu<strong>la</strong>ted byhypoxia in human breast cancer cells MCF-7 and MDA-MB-231. BiomedPharmacother, 57: 333-340, 2003.36. Hu, K., Yang, J., Tanaka, S., Gonias, S. L., Mars, W. M., and Liu, Y. Tissu<strong>et</strong>ypep<strong>la</strong>sminogen activator acts as a cytokine that triggers intracellu<strong>la</strong>r signaltrans<strong>du</strong>ction and in<strong>du</strong>ces matrix m<strong>et</strong>alloproteinase-9 gene expression. J BiolChem, 281: 2120-2127, 2006.37. Boucher, P. and Gotthardt, M. LRP and PDGF signaling: a pathway toatherosclerosis. Trends Cardiovasc Med, 14: 55-60, 2004.38. Boucher, P., Liu, P., Gotthardt, M., Hiesberger, T., An<strong>de</strong>rson, R. G., and Herz,J. P<strong>la</strong>tel<strong>et</strong>-<strong>de</strong>rived growth factor mediates tyrosine phosphory<strong>la</strong>tion of thecytop<strong>la</strong>smic domain of the low Density lipoprotein receptor-re<strong>la</strong>ted protein incaveo<strong>la</strong>e. J Biol Chem, 277: 15507-15513, 2002.39. Yang, M., Huang, H., Li, J., Li, D., and Wang, H. Tyrosine phosphory<strong>la</strong>tion ofthe LDL receptor-re<strong>la</strong>ted protein (LRP) and activation of the ERK pathway arerequired for connective tissue growth factor to potentiate myofibrob<strong>la</strong>stdifferentiation. Faseb J, 18: 1920-1921, 2004.40. Barnes, H., Ackermann, E. J., and van <strong>de</strong>r Geer, P. v-Src in<strong>du</strong>ces Shc bindingto tyrosine 63 in the cytop<strong>la</strong>smic domain of the LDL receptor-re<strong>la</strong>ted protein 1.Oncogene, 22: 3589-3597, 2003.41. May, P., Reddy, Y. K., and Herz, J. Proteolytic processing of low <strong>de</strong>nsitylipoprotein receptor-re<strong>la</strong>ted protein mediates regu<strong>la</strong>ted release of itsintracellu<strong>la</strong>r domain. J Biol Chem, 277: 18736-18743, 2002.22
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Université Montpellier I UFR Méd
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Un grand merci à tous mes collabor
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TitleBreast cancer and tumoral micr
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Cancer du sein et micro-environneme
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C. PRESENTATION DU TRAVAIL DE THESE
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But de la thèseLa cathepsine-D (ca
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I. Le tissu adipeux1) Généralité
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(Adenosine triphosphate). Cette pro
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Cette synthèse de novo a lieu dans
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ABFigure 6 : Schéma de la oxydati
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d. Ladipocyte : une cellule sécré
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3) Ladipogenèsea. Les différentes
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. Les facteurs de transcriptionLa d
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Lexpression de C/EBP est quant à e
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adipeux. Les analyses histologiques
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adipocyteFigure 10 : Schéma repré
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II. La cathepsine-D1) Synthèse, ma
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les cath-B et L, en une forme matur
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Il existe deux RM6P : le RM6P/IGFII
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2) Fonctions de la cath-Da. Dans la
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. Dans les pathologiesEn plus de se
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c. Rôles et mécanismes daction da
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carcinome de prostate serait respon
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La cath-D joue donc un rôle import
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Une fois le marquage des peptides e
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Afin de réaliser ce projet, nous a
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III. Le récepteur LRP11) Organisat
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2) Trafic intra-cellulaireComme le
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LRP1αLRP1Membrane associatedprotea
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Tableau 3 : Ligands connus du LRP1(
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I. Etude du rôle de la cathepsine
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Cathepsin-D, a key protease in brea
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IntroductionConsumption of meals ri
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(Fig. 1A, panel a). This differenti
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differentiated adipocyte (Fig. 4B).
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DiscussionOur results demonstrate t
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from normal and peri-al breast adip
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mouse RS9 (sens 5CGGCCCGGGAGCTGTTGA
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agreement of local ethic committee.
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Statistical analysis. Results are e
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Loncarek J, Freiss G, Vignon F and
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Aa3000 *b4000*B8000**cath-D mRNA(ar
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ABcath-D mRNA(ratio RS9)PPARg mRNA(
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A D3 D7 D14D0BaD0 D3 D7 D14D0 D3 D7
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AshLucshcath-DF442A C34 C37 A4 D10c
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AF442-AC34C37A4D10BF442-AC34C37A4D1
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II. Etude du rôle du LRP1 dans les
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2) Article 2:LRP1 receptor controls
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LRP1, Adipogenesis, Obesityrelative
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LRP1, Adipogenesis, ObesityFigure 3
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LRP1, Adipogenesis, ObesityFigure 5
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LRP1, Adipogenesis, ObesitySome ins
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LRP1, Adipogenesis, ObesityLipolysi
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CONCLUSIONLa cathepsine D (cath-D)
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- Page 112 and 113: carcinogénique sont encore mal con
- Page 114 and 115: Ce travail de thèse a étudié, po
- Page 116 and 117: REFERENCESAhima, R. S. (2006). Adip
- Page 118 and 119: implicates them as antigen presenti
- Page 120 and 121: Cataldo, A. M., Barnett, J. L., Ber
- Page 122 and 123: Folkman, J. (2003). Fundamental con
- Page 124 and 125: Hofmann, S. M., Zhou, L., Perez-Til
- Page 126 and 127: Langin, D. (2006a). Adipose tissue
- Page 128 and 129: Ludwig, T., Ovitt, C. E., Bauer, U.
- Page 130 and 131: Nirde, P., Derocq, D., Maynadier, M
- Page 132 and 133: Rozanov, D. V., Hahn-Dantona, E., S
- Page 134 and 135: Taleb, S., Cancello, R., Clement, K
- Page 136 and 137: Xiao, Y., Junfeng, H., Tianhong, L.
- Page 138 and 139: F. ANNEXE98
- Page 140 and 141: Cathepsin D is a new ligand for ext
- Page 142 and 143: INTRODUCTIONLysosomal aspartic prot
- Page 144 and 145: pcDNA3.1(+)Myc-tagged LRP1b into pc
- Page 146 and 147: (Protein refolding kit, Novagen) fo
- Page 148 and 149: anti-mouse-gold (Aurion). Sections
- Page 150 and 151: not secrete detectable levels of pr
- Page 152 and 153: using cath-D-/- MEF transfected wit
- Page 154 and 155: co-culture outgrowth assays with ca
- Page 156 and 157: REFERENCES1. Vignon, F., Capony, F.
- Page 158 and 159: steps in vivo: proliferation, angio
- Page 162 and 163: 42. Zurhove, K., Nakajima, C., Herz
- Page 164 and 165: Figure 1. Cath-D interacts with the
- Page 166 and 167: Figure 2. Cath-D binds to residues
- Page 168 and 169: Figure 3. Cath-D interacts with LRP
- Page 170 and 171: Figure 5. Silencing LRP1 in cath-D
- Page 172 and 173: Figure 1. Cath-D interacts with the
- Page 174 and 175: Figure 6. LRP1 is the receptor medi
- Page 176 and 177: Beaujouin, Figure Sup. 2cath-D-/-ME
- Page 178: RésuméLaspartyl protéase catheps