Role of transglutaminase II in retinoic acid-induced activation of RhoA-associated kinase-2

Singh, Uaday; Kunar, Matthew T.; Kao, Yu‐Lin; Baker, Kenneth M.

doi:10.1093/emboj/20.10.2413

Cited by 79 publications

(95 citation statements)

References 68 publications

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“…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). To better understand the anti-apoptotic activity of TGase, we wanted to examine its interactions with substrates that may be involved in the regulation of apoptosis.…”

Section: Resultsmentioning

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

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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%

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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“…RA is essential in inducing RhoA and in its binding to Rock and activation of Rock kinase activity (44)(45)(46). Members of the Rho family of small GTP-binding proteins are key regulators of cytoskeletal changes, cell motility, and cell invasion (47).…”

Section: Discussionmentioning

confidence: 99%

β-Escin Inhibits NNK-Induced Lung Adenocarcinoma and ALDH1A1 and RhoA/Rock Expression in A/J Mice and Growth of H460 Human Lung Cancer Cells

Patlolla

Biddick

et al. 2013

Cancer Prevention Research

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Lung cancer is the leading cause of cancer-related deaths. b-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of lung adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 mmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 b-escin) or 36 weeks (15 control, 5 b-escin) and evaluated for lung tumor via histopathologic methods. Administration of 500 ppm b-escin significantly suppressed lung tumor (adenoma þ adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. b-Escin inhibited NNK-induced lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that lung tumors from mice exposed to b-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 lung cancer cells treated with different concentrations of b-escin (0-40 mmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that b-escin inhibits tobacco carcinogeninduced lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling. Cancer Prev Res; 6(10);

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“…These observations and our current findings clearly suggest that TG2 expression promotes the cell migration and invasion functions in breast cancer cells. It is possible that alterations such as the constitutive activation of small GTPase RhoA caused by the transamidation reaction catalysed by cytoplasmic TG2 (Singh et al, 2001) or the integrin aggregation induced by cell surface TG2 alter cytoskeletal organization and contribute to the increased ability of TG2-expressing metastatic cells to adhere and migrate. A further understanding of TG2-mediated cellular interactions with the ECM and signaling pathways induced in response to such an interaction may offer new targets for intervention and treatment of metastatic cancer.…”

Section: Tg2 Expression and Metastasis Ls Mangala Et Almentioning

confidence: 99%

Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells

et al. 2006

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Distant metastasis is frequently observed in patients with breast cancer and is a major cause of cancer-related deaths in these patients. Currently, very little is known about the mechanisms that underlie the development of the metastatic phenotype in breast cancer cells. We previously found that metastatic breast cancer cells express high levels of tissue transglutaminase (TG2), but established no direct link between TG2 and metastasis. In this study, we hypothesized that TG2 plays a role in conferring the metastatic phenotype to breast cancer cells. The results obtained suggested that increased expression of TG2 in breast cancer cells contributes to their increased survival, invasion and motility. We further found that TG2 protein in a metastatic breast cancer MDA-MB231 cells was present on the cell surface in close association with integrins b1, b4 and b5. Downregulation of endogenous TG2 by small interfering RNA inhibited fibronectin (Fn)-mediated cell attachment, survival and invasion. Conversely, ectopic expression of TG2 augmented invasion of breast cancer cells and attachment to Fn-coated surfaces. We conclude that TG2 expression in breast cancer cells plays an important role in the development of the metastatic phenotype.

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Role of transglutaminase II in retinoic acid-induced activation of RhoA-associated kinase-2

Cited by 79 publications

References 68 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

β-Escin Inhibits NNK-Induced Lung Adenocarcinoma and ALDH1A1 and RhoA/Rock Expression in A/J Mice and Growth of H460 Human Lung Cancer Cells

Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells

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