Identification of Cytoplasmic Actin as an Abundant Glutaminyl Substrate for Tissue Transglutaminase in HL-60 and U937 Cells Undergoing Apoptosis

Nemes, Zoltán; Ádány, Róza; Balázs, Margit; Boross, Péter; Fésüs, László

doi:10.1074/jbc.272.33.20577

Cited by 101 publications

(67 citation statements)

References 44 publications

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“…Tissue transglutaminase (TGase) has been shown to be upregulated in cells undergoing apoptosis, raising the possibility that it is a pro-apoptotic protein (7)(8)(9)(10)(13)(14)(15)(16). However, recent studies examining the role of TGase in RA-mediated differentiation have shown that it provides protection against apoptosis (12) and may be important for cellular differentiation (19,33).…”

Section: Resultsmentioning

confidence: 99%

“…The transamidation reaction of TGase has been well studied and consists of the Ca 2ϩ -dependent formation of covalent bonds between the ␥-carboxamide groups of peptide-bound glutamine residues and the primary amino groups of a wide variety of proteins (1,2). Transamidation has been implicated in a number of biological processes such as axonal regeneration, cellular differentiation, and apoptosis (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Many of the early studies of TGase have identified it as being present in cells and tissues undergoing apoptosis (7-10, 13, 14) and implicated the transamidation activity of TGase as a potentiator of programmed cell death (15,16).…”

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confidence: 99%

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Tissue Transglutaminase Protects against Apoptosis by Modifying the Tumor Suppressor Protein p110 Rb

Boehm

Singh

Combs

et al. 2002

Journal of Biological Chemistry

111

123

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Tissue transglutaminase or type II transglutaminase (TGase) 1 is an 87-kDa protein that contains two key catalytic activities, the ability to catalyze protein-amine cross-links and a GTP binding and hydrolysis activity. The transamidation reaction of TGase has been well studied and consists of the Ca 2ϩ -dependent formation of covalent bonds between the ␥-carboxamide groups of peptide-bound glutamine residues and the primary amino groups of a wide variety of proteins (1, 2). Transamidation has been implicated in a number of biological processes such as axonal regeneration, cellular differentiation, and apoptosis (3-12). Many of the early studies of TGase have identified it as being present in cells and tissues undergoing apoptosis (7-10, 13, 14) and implicated the transamidation activity of TGase as a potentiator of programmed cell death (15,16). However, there is growing evidence that TGase may not directly mediate apoptosis. TGase Ϫ/Ϫ mice showed no major developmental abnormalities, and the thymocytes from these mice were no less susceptible to apoptosis than TGase ϩ/ϩ cells (17,18). Studies examining the role of TGase in retinoic acid (RA)-mediated signaling (12), as well as studies demonstrating that TGase was required for neurite outgrowth (19), suggest that TGase may exhibit protective effects against apoptotic signals. It has been well documented that RA up-regulates both the expression and transamidation activity of TGase (12, 20 -22). We have recently shown that the ability of RA to up-regulate TGase expression and activity is required for the ability of RA to protect against apoptosis induced by a synthetic retinoid analog, all-trans-N-(4-hydroxyphenyl)retinamide (HPR) (12). The TGase-mediated inhibition of apoptosis appeared to involve its transamidation activity and its ability to bind GTP (12), a result that may suggest a role for TGase in more than one anti-apoptotic signaling pathway.To understand how TGase is acting as an anti-apoptotic factor, we set out to investigate substrates of TGase that are potential regulators of cell death. One such protein was the retinoblastoma gene product (Rb), a well established regulator of the G 1 /S checkpoint in the cell cycle (23)(24)(25). In addition to its role in cell cycle regulation and cellular differentiation, Rb has also been implicated in apoptosis (26). Rb Ϫ/Ϫ mice are embryonic lethal with significant apoptosis occurring in the developing nervous system and lens of the eye (27-30). The tumor suppressor gene p53 activates a pathway in response to various cellular insults that results in the degradation of Rb (31), a critical event that shifts cells toward apoptosis. The Rb protein was initially identified as a substrate for TGase-mediated transamidation in U937 cells in early stages of apoptosis (11). This finding, when combined with other results showing increased expression of TGase in apoptotic cells (7-10, 13, 14), led to the suggestion that TGase was a pro-apoptotic protein. However, we have found that TGase acts in a protective fashion (12) b...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Tissue Transglutaminase Protects against Apoptosis by Modifying the Tumor Suppressor Protein p110 Rb

Boehm

Singh

Combs

et al. 2002

Journal of Biological Chemistry

111

123

View full text Add to dashboard Cite

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“…The cytoskeleton and cell walls may be responsible for this change of shape. In analogy with the animal cell, 52 it is known that also in plants cytoskeletal proteins are targets for TGases, as shown during apical growth of pollen tubes, where actin and tubulin are modified by PAs. 24 Starting from stage 6 when senescence begins, a relevant event takes place in the corolla, i.e.…”

Section: Corolla Of Undetached¯owersmentioning

confidence: 99%

Transglutaminase activity during senescence and programmed cell death in the corolla of tobacco (Nicotiana tabacum) flowers

et al. 2002

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Corolla life span of undetached flowers of Nicotiana tabacum was divided into stages from the closed corolla (stage 1) through anthesis (stage 5) to death (stage 9). Senescence began around stage 6 in the proximal part, concomitantly with DNA laddering. Nuclear blebbing, DNA laddering, cell wall modification, decline in protein, water, pigment content and membrane integrity were observed during senescence and PCD. Transglutaminase activity was measured as mono-and bis-derivatives of putrescine (mono-PU; bis-PU) and bis-derivatives of spermidine (bis-SD). Bis-derivatives decreased with the progression of senescence, while mono-PU increased during early senescence; derivatives were present in different amounts in the proximal and distal parts of the corolla. In excised flowers, exogenous spermine delayed senescence and PCD, and caused an increase in free and acid-soluble conjugated PA levels. Bis-PU was the most abundant PA-derivative before DNA laddering stage; thereafter, bis-PU generally decreased and mono-PU became the most abundant derivative.

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“…One aspect of TGase regulation involves altering the expression levels of the protein. In several cell types, the TGase protein is expressed at low levels (4,7,15), and increases in TGase expression and activation can be induced following chronic stimulation with growth factors (16), chemotherapeutic agents (17), cytokines (18), and retinoids (19). Retinoic acid (RA) is the most consistent inducer of TGase expression and activation, and a mechanism by which RA upregulates TGase expression has been elucidated.…”

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confidence: 99%

Activation of the Ras-ERK Pathway Inhibits Retinoic Acid-induced Stimulation of Tissue Transglutaminase Expression in NIH3T3 Cells

Antonyak

McNeill

Wakshlag

et al. 2003

Journal of Biological Chemistry

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Retinoic acid (RA) is a potent activator of tissue transglutaminase (TGase) expression, and it was recently shown that phosphoinositide 3-kinase (PI3K) activity was required for RA to increase TGase protein levels. To better understand how RA-mediated TGase expression is regulated, we considered whether co-stimulation of NIH3T3 cells with RA and epidermal growth factor (EGF), a known activator of PI3K, would facilitate the induction or increase the levels of TGase expression. Instead of enhancing these parameters, EGF inhibited RA-induced TGase expression. Activation of the Ras-ERK pathway by EGF was sufficient to elicit this effect, since continuous Ras signaling mimicked the actions of EGF and inhibited RA-induced TGase expression, whereas blocking ERK activity in these same cells restored the ability of RA to up-regulate TGase expression. However, TGase activity is not antagonistic to EGF signaling. The mitogenic and anti-apoptotic effects of EGF were not compromised by TGase overexpression, and in fact, exogenous TGase expression promoted basal cell growth and resistance to serum deprivation-induced apoptosis. Moreover, analysis of TGase expression and GTP binding activity in a number of cell lines revealed high basal TGase GTP binding activity in tumor cell lines U87 and MDAMB231, indicating that constitutively active TGase may be a characteristic of certain cancer cells. These findings demonstrate that TGase may serve as a survival factor and RA-induced TGase expression requires the activation of PI3K but is antagonized by the Ras-ERK pathway.

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Identification of Cytoplasmic Actin as an Abundant Glutaminyl Substrate for Tissue Transglutaminase in HL-60 and U937 Cells Undergoing Apoptosis

Cited by 101 publications

References 44 publications

Tissue Transglutaminase Protects against Apoptosis by Modifying the Tumor Suppressor Protein p110 Rb

Tissue Transglutaminase Protects against Apoptosis by Modifying the Tumor Suppressor Protein p110 Rb

Transglutaminase activity during senescence and programmed cell death in the corolla of tobacco (Nicotiana tabacum) flowers

Activation of the Ras-ERK Pathway Inhibits Retinoic Acid-induced Stimulation of Tissue Transglutaminase Expression in NIH3T3 Cells

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