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Molecular and Cellular Biology, January 2001, p. 148-155, Vol. 21, No. 1
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.1.148-155.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Gene Disruption of Tissue Transglutaminase

Vincenzo De Laurenzi and Gerry Melino*

IDI-IRCCS Biochemistry Lab, Department of Experimental Medicine, University Tor Vergata, Rome, Italy

Received 20 July 2000/Returned for modification 12 September 2000/Accepted 28 September 2000

Transglutaminase 2 (TGase 2), or tissue transglutaminase, catalyzes either varepsilon -(gamma -glutamyl)lysine or N1,N8-(gamma -glutamyl)spermidine isopeptide bonds. TGase 2 expression has been associated with apoptosis, and it has been proposed that its activation should lead to the irreversible assembly of a cross-linked protein scaffold in dead cells. Thus, TGase 2-catalyzed protein polymerization contributes to the ultrastructural changes typical of dying apoptotic cells; it stabilizes the integrity of the apoptotic cells, preventing the release of harmful intracellular components into the extracellular space and, consequently, inflammation and scar formation. In order to perform a targeted disruption of the enzyme, we prepared a construct deleting part of exons 5 and 6, containing the active site, and intron 5. Complete absence of TGase 2 was demonstrated by reverse transcription-PCR and Western blot analysis. TGase activity measured on liver and thymus extracts showed, however, a minimal residual activity in TGase 2-/- mice. PCR analysis of mRNA extracted from the same tissues demonstrated that at least TGase 1 (normally present in the skin) is also expressed in these tissues and contributes to this residual activity. TGase 2-/- mice showed no major developmental abnormalities, and histological examination of the major organs appeared normal. Induction of apoptosis ex vivo in TGase 2-/- thymocytes (by CD95, dexamethasone, etoposide, and H2O2) and in vitro on TGase 2-/- mouse embryonal fibroblasts (by retinoids, UV, and H2O2) showed no significant differences. A reduction in cross-linked apoptotic bodies with a modestly increased release of lactate dehydrogenase has been detected in some cases. Together our results show that TGase 2 is not a crucial component of the main pathway of the apoptotic program. It is possible that the residual enzymatic activity, due to TGase 1 or redundancy of other still-unidentified TGases, can compensate for the lack of TGase 2.

* Corresponding author. Mailing address: IDI-IRCCS, Biochemistry Lab, c/o Dep. Experimental Medicine, D26/F153, University of Rome Tor Vergata, Via Tor Vergata 135, 00133 Rome, Italy. Phone: 39 6 20427299. Fax: 39 6 20427290. E-mail: gerry.melino{at}uniroma2.it.

Molecular and Cellular Biology, January 2001, p. 148-155, Vol. 21, No. 1
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.1.148-155.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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