Gene Disruption of Tissue Transglutaminase

doi:10.1128/MCB.21.1.148-155.2001

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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 hasbeen associated with apoptosis, and it has been proposed thatits activation should lead to the irreversible assembly of a cross-linkedprotein scaffold in dead cells. Thus, TGase 2-catalyzed proteinpolymerization contributes to the ultrastructural changes typicalof dying apoptotic cells; it stabilizes the integrity of the apoptoticcells, preventing the release of harmful intracellular componentsinto the extracellular space and, consequently, inflammation andscar formation. In order to perform a targeted disruption of theenzyme, we prepared a construct deleting part of exons 5 and 6,containing the active site, and intron 5. Complete absence ofTGase 2 was demonstrated by reverse transcription-PCR and Westernblot analysis. TGase activity measured on liver and thymus extractsshowed, however, a minimal residual activity in TGase 2^/ mice. PCR analysis of mRNA extracted from the same tissues demonstratedthat at least TGase 1 (normally present in the skin) is also expressedin these tissues and contributes to this residual activity. TGase2^/ mice showed no major developmental abnormalities, and histologicalexamination of the major organs appeared normal. Induction ofapoptosis ex vivo in TGase 2^/ thymocytes (by CD95, dexamethasone, etoposide, and H₂O₂) andin vitro on TGase 2^/ mouse embryonal fibroblasts (by retinoids, UV, and H₂O₂) showedno significant differences. A reduction in cross-linked apoptoticbodies with a modestly increased release of lactate dehydrogenasehas been detected in some cases. Together our results show thatTGase 2 is not a crucial component of the main pathway of theapoptotic program. It is possible that the residual enzymaticactivity, due to TGase 1 or redundancy of other still-unidentifiedTGases, can compensate for the lack of TGase2.

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

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