publication . Thesis

Understanding the link between transglutaminase and the induction of fibrosis in cystic fibrosis (CF)

Nyabam, Samuel;
Open Access English
  • Country: United Kingdom
Abstract
The emerging role of the multifunctional enzyme, Transglutaminase 2 (TG2) in Cystic Fibrosis (CF) has been linked to its increased expression and intracellular transamidating activity. However, a full understanding of the molecular mechanisms involved still remains unclear despite numerous studies that have attempted to delineate this process. These mechanisms include the NFκB and TGFβ1 pathway amongst others. This study reveals for the first time that the development of fibrosis in CF is due to a TG2-driven epithelial to mesenchymal transition (EMT) via a mechanism involving the activation of the pro-fibrotic cytokine TGFβ1. Using a human ΔF508/W1282X CFTR CF m...
Related Organizations
60 references, page 1 of 4

4.3.4.1:!Reversal!of!TG2!expression!restores!epithelial!phenotype!in!IB3!cells !..........!119! 4.3.4.2:!Inhibition!of!TGFβ1!ameliorates!EMT!in!CF!................................................................!124! 4.3.5:*TG2*involvement*in*the*activation*of*TGFβ1*by*the*integrin,*αVβ6.*............*125! 4.3.6:*TG2\TGFβ1*induced*EMT*is*SMAD*dependent*....................................................*129! 5.4.1.1:!NRcadherin!expression!is!transiently!abolished!in!the!presence!of!siRNAs. !.!142! 5.4.1.2:!Stable!knockdown!of!TG2!mimics!TG2!inhibition!and!abrogates!EMT!...........!144! 5.4.2:*Mutation*at*the*TG2*transamidation*active*site*and*the*GTPase*site*unveils* the*function*of*TG2*in*EMT.*...................................................................................................*148! fibronectin-binding site in its N-terminal beta-sandwich domain. J Biol Chem, 274, 30707-14.

Gaudry, C. A., Verderio, E., Jones, R. A., Smith, C. & Griffin, M. 1999b. Tissue transglutaminase is an important player at the surface of human endothelial cells: evidence for its externalisation and its colocalisation with the beta(1) integrin. Exp Cell Res, 252, 104-13.

George, M. D., Vollberg, T. M., Floyd, E. E., Stein, J. P. & Jetten, A. M. 1990. Regulation of transglutaminase type II by transforming growth factor-beta 1 in normal and transformed human epidermal keratinocytes. J Biol Chem, 265, 11098-104. [OpenAIRE]

Graff, J. M., Bansal, A. & Melton, D. A. 1996. Xenopus Mad proteins transduce distinct subsets of signals for the TGF beta superfamily. Cell, 85, 479-87. [OpenAIRE]

Grainger, C. I., Greenwell, L. L., Lockley, D. J., Martin, G. P. & Forbes, B. 2006. Culture of Calu-3 Cells at the Air Interface Provides a Representative Model of the Airway Epithelial Barrier. Pharmaceutical Research, 23, 1482-1490.

Grande, J. P. 1997. Role of transforming growth factor-beta in tissue injury and repair. Proc Soc Exp Biol Med, 214, 27-40.

Grande, M., Franzen, A., Karlsson, J. O., Ericson, L. E., Heldin, N. E. & Nilsson, M. 2002. Transforming growth factor-beta and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. J Cell Sci, 115, 4227-36.

Greenberg, C. S., Birckbichler, P. J. & Rice, R. H. 1991. Transglutaminases: multifunctional crosslinking enzymes that stabilize tissues. FASEB J, 5, 3071-7.

Griffin, M., Casadio, R. & Bergamini, C. M. 2002. Transglutaminases: nature's biological glues. Biochem J, 368, 377-96.

Griffin, M., Mongeot, A., Collighan, R., Saint, R. E., Jones, R. A., Coutts, I. G. & Rathbone, D. L. 2008. Synthesis of potent water-soluble tissue transglutaminase inhibitors. Bioorg Med Chem Lett, 18, 5559-62. [OpenAIRE]

Griffin, M., Smith, L. L. & Wynne, J. 1979. Changes in transglutaminase activity in an experimental model of pulmonary fibrosis induced by paraquat. Br J Exp Pathol, 60, 653-61. [OpenAIRE]

Griffith, L. G. & Swartz, M. A. 2006. Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol, 7, 211-24.

Grosso, H. & Mouradian, M. M. 2012. Transglutaminase 2: biology, relevance to neurodegenerative diseases and therapeutic implications. Pharmacol Ther, 133, 392-410.

Moreno-Bueno, G., Cubillo, E., Sarrio, D., Peinado, H., Rodriguez-Pinilla, S. M., Villa, S., Bolos, V., Jorda, M., Fabra, A., Portillo, F., Palacios, J. & Cano, A. 2006. Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial-mesenchymal transition. Cancer Res, 66, 9543-56.

Mu, D., Cambier, S., Fjellbirkeland, L., Baron, J. L., Munger, J. S., Kawakatsu, H., Sheppard, D., Broaddus, V. C. & Nishimura, S. L. 2002. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol, 157, 493-507. [OpenAIRE]

60 references, page 1 of 4
Abstract
The emerging role of the multifunctional enzyme, Transglutaminase 2 (TG2) in Cystic Fibrosis (CF) has been linked to its increased expression and intracellular transamidating activity. However, a full understanding of the molecular mechanisms involved still remains unclear despite numerous studies that have attempted to delineate this process. These mechanisms include the NFκB and TGFβ1 pathway amongst others. This study reveals for the first time that the development of fibrosis in CF is due to a TG2-driven epithelial to mesenchymal transition (EMT) via a mechanism involving the activation of the pro-fibrotic cytokine TGFβ1. Using a human ΔF508/W1282X CFTR CF m...
Related Organizations
60 references, page 1 of 4

4.3.4.1:!Reversal!of!TG2!expression!restores!epithelial!phenotype!in!IB3!cells !..........!119! 4.3.4.2:!Inhibition!of!TGFβ1!ameliorates!EMT!in!CF!................................................................!124! 4.3.5:*TG2*involvement*in*the*activation*of*TGFβ1*by*the*integrin,*αVβ6.*............*125! 4.3.6:*TG2\TGFβ1*induced*EMT*is*SMAD*dependent*....................................................*129! 5.4.1.1:!NRcadherin!expression!is!transiently!abolished!in!the!presence!of!siRNAs. !.!142! 5.4.1.2:!Stable!knockdown!of!TG2!mimics!TG2!inhibition!and!abrogates!EMT!...........!144! 5.4.2:*Mutation*at*the*TG2*transamidation*active*site*and*the*GTPase*site*unveils* the*function*of*TG2*in*EMT.*...................................................................................................*148! fibronectin-binding site in its N-terminal beta-sandwich domain. J Biol Chem, 274, 30707-14.

Gaudry, C. A., Verderio, E., Jones, R. A., Smith, C. & Griffin, M. 1999b. Tissue transglutaminase is an important player at the surface of human endothelial cells: evidence for its externalisation and its colocalisation with the beta(1) integrin. Exp Cell Res, 252, 104-13.

George, M. D., Vollberg, T. M., Floyd, E. E., Stein, J. P. & Jetten, A. M. 1990. Regulation of transglutaminase type II by transforming growth factor-beta 1 in normal and transformed human epidermal keratinocytes. J Biol Chem, 265, 11098-104. [OpenAIRE]

Graff, J. M., Bansal, A. & Melton, D. A. 1996. Xenopus Mad proteins transduce distinct subsets of signals for the TGF beta superfamily. Cell, 85, 479-87. [OpenAIRE]

Grainger, C. I., Greenwell, L. L., Lockley, D. J., Martin, G. P. & Forbes, B. 2006. Culture of Calu-3 Cells at the Air Interface Provides a Representative Model of the Airway Epithelial Barrier. Pharmaceutical Research, 23, 1482-1490.

Grande, J. P. 1997. Role of transforming growth factor-beta in tissue injury and repair. Proc Soc Exp Biol Med, 214, 27-40.

Grande, M., Franzen, A., Karlsson, J. O., Ericson, L. E., Heldin, N. E. & Nilsson, M. 2002. Transforming growth factor-beta and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. J Cell Sci, 115, 4227-36.

Greenberg, C. S., Birckbichler, P. J. & Rice, R. H. 1991. Transglutaminases: multifunctional crosslinking enzymes that stabilize tissues. FASEB J, 5, 3071-7.

Griffin, M., Casadio, R. & Bergamini, C. M. 2002. Transglutaminases: nature's biological glues. Biochem J, 368, 377-96.

Griffin, M., Mongeot, A., Collighan, R., Saint, R. E., Jones, R. A., Coutts, I. G. & Rathbone, D. L. 2008. Synthesis of potent water-soluble tissue transglutaminase inhibitors. Bioorg Med Chem Lett, 18, 5559-62. [OpenAIRE]

Griffin, M., Smith, L. L. & Wynne, J. 1979. Changes in transglutaminase activity in an experimental model of pulmonary fibrosis induced by paraquat. Br J Exp Pathol, 60, 653-61. [OpenAIRE]

Griffith, L. G. & Swartz, M. A. 2006. Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol, 7, 211-24.

Grosso, H. & Mouradian, M. M. 2012. Transglutaminase 2: biology, relevance to neurodegenerative diseases and therapeutic implications. Pharmacol Ther, 133, 392-410.

Moreno-Bueno, G., Cubillo, E., Sarrio, D., Peinado, H., Rodriguez-Pinilla, S. M., Villa, S., Bolos, V., Jorda, M., Fabra, A., Portillo, F., Palacios, J. & Cano, A. 2006. Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial-mesenchymal transition. Cancer Res, 66, 9543-56.

Mu, D., Cambier, S., Fjellbirkeland, L., Baron, J. L., Munger, J. S., Kawakatsu, H., Sheppard, D., Broaddus, V. C. & Nishimura, S. L. 2002. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol, 157, 493-507. [OpenAIRE]

60 references, page 1 of 4
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