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1. Introduction
*
Corresponding author. Fax: +36 52 314 989.
E-mail addresses: fesus@indi.dote.hu (L. Fesus), szondy@indi.dote.hu
(Z. Szondy).
Abbreviations: EGF, epidermal growth factor; HPR, N-(hydroxyphenyl)retinamide; Rb, retinoblastoma protein; TG, transglutaminase;
TGFb, tumor growth factor b
0014-5793/$30.00 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.febslet.2005.03.063
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The above results clearly suggest that TG2 has the capability
both to facilitate and to prevent apoptosis. These two opposing activities may be separated in the sense that each occurs
distinctly depending on the specic biochemical pathways of
apoptosis in dierent cell types, the kind of stimuli, the intracellular localization of the enzyme and the type of activity of
TG2 switched on. It has been proposed that the observed
upregulation of TG2 in some cells dying by apoptosis upon
distinct stimuli is a cellular regulatory mechanism to block
or delay the onset of death rather than reecting a direct participation of the enzyme in apoptosis [33]. On the other hand,
the BH3 domain of TG2 can clearly mediate cell death at the
mitochondrial level in other types of cells. TG2Bax interaction might be anti-apoptotic at rst by blocking Bax action
on the mitochondria and preventing cytochrome c release
[23]. After apoptosis induction, however, the calcium-activated
TG2 polymerizes Bax to a pore-forming complex. Alternatively, it cannot be excluded that the TG2Bax complex is already proapoptotic similarly to other BH3-only proteins
without transamidating activity, and transamidation results
only in further stabilization of the proapoptotic conformation.
It has also been shown that TG2 modulates apoptosis in a
stimulus-dependent manner [35]. It potentiates apoptosis in response to osmotic stress with increased in situ transamidating
activity, and protects cells against heat shock-induced apoptosis without increased transamidation, very likely acting as a G
protein.
Johnson and her co-workers [36] have designed experiments
to see how the intracellular localization and transamidating
activity of TG2 modulates its eect on thapsigargin-induced
apoptosis. These studies utilized externally added TG2 variants targeting dierent cellular compartments and it was found
that cytosolic TG2 was pro-apoptotic by virtue of its transamidating activity. On the other hand, its nuclear localization
attenuated apoptosis in human embryonic kidney cells without
a requirement for transamidation but being dependent on a
non-covalent interaction between TG2 and Rb as opposed to
the need of transamidation of RB to protect human promyelocytic leukemia cells [33].
Secreted TG2 can protect cells from anoikis in an RGD
independent manner without a requirement for the G protein
or the transamidating activity [26]. Regarding transamidation
and G protein function the so far published data show that
the G form of the enzyme has not been found proapoptotic
in any system while its transamidating activity was more often
required for facilitating cell death than for survival. One cannot exclude the possibility that the newly discovered biochemical properties of TG2, namely its protein disulde isomerase
and protein kinase activity [6,7], are also important in determining how TG2 inuences cell death.
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which TG2 can achieve this goal (Fig. 1). It promotes apoptosis by either direct mechanism in certain apoptotic cells
[19,20,23], or indirectly by promoting activation of TGFb released by macrophages that can promote the death of various
cells [14,51]. This ensures that all the unwanted cells are killed
and fast without leading to necrosis. In apoptotic cells TG2
also promotes the formation of chemoattractants [46] and
the exposure of phosphatidylserine that facilitate migration
of macrophages to the apoptosis site and recognition of apoptotic cells, respectively. TG2 also participates in the activation
of TGFb which is required for the in vivo induction of TG2 in
both macrophages and apoptotic cells [14,52]. TG2-dependent
crosslinking of proteins and formation of protective protena-
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