Retinoic Acid–Induced Tissue Transglutaminase and Apoptosis in Vascular Smooth Muscle Cells

Ou, Hesheng; Haendeler, Judith; Aebly, Michael R.; Kelly, Louise A.; Cholewa, Brian C.; Koike, George; Kwitek, Anne E.; Jacob, Howard J.; Berk, Bradford C.; Miano, Joseph M.

doi:10.1161/01.res.87.10.881

Cited by 53 publications

(55 citation statements)

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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%

“…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). However, there is growing evidence that TGase may not directly mediate apoptosis.…”

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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

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“…[5][6][7] ATRA also induced favorable remodeling of the injured artery in rabbits. 8 In cultured aortic smooth muscle cells, ATRA induced apoptosis 9 and inhibited proliferation induced by serotonin, 10 platelet-derived growth factor, 11 endothelin-1, 12 and angiotensin II. 13 The suppression of smooth muscle cell proliferation by ATRA depends on retinoic acid receptors.…”

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confidence: 99%

Retinoids and Pulmonary Hypertension

et al. 2005

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Background-Retinoic acid has antimitogenic effects on smooth muscle cells. Studies on the systemic circulation suggest that it may reduce vascular thickening. Relationships between retinoids and pulmonary hypertension/pulmonary vascular remodeling, however, have not been explored. Thus, the present study examined retinoid levels in plasma of patients with idiopathic pulmonary arterial hypertension and the effects of retinoic acid on human pulmonary artery smooth muscle cell growth. Methods and Results-We measured retinoid levels by gas chromatograph-mass spectrometer technique in plasma of idiopathic pulmonary arterial hypertension patients and in age-and sex-matched healthy control subjects. Patients had significantly lower levels of all-trans retinoic acid and 13-cis retinoic acid than control subjects but similar 9-cis retinoic acid and retinol levels. In cultured human pulmonary artery smooth muscle cells, all-trans retinoic acid suppressed serotonin-induced cell growth. These cells were found to express the retinoid acid receptors RAR␣, RAR␤, RAR␥, RXR␣, and RXR␤. Gene array analysis showed that retinoic acid induces the expression of GADD45A, a known cell growth suppressor. Contrary to expectations, plasma from pulmonary hypertension patients suppressed cell growth, likely influenced by factors other than retinoids. Conclusions-Idiopathic

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“…Retinoids downregulate angiotensin II (AII) type 1 receptor expression in VSMCs, resulting in the inhibition of AII actions on VSMCs (24,25). Retinoids have also been reported to induce apoptosis in VSMCs (26,27). Incubation of multipotential P19 embryonal carcinoma cells with retinoids induces differentiation of VSMCs through the induction of α-smooth muscle actin (28,29).…”

Section: Discussionmentioning

confidence: 99%

Transcription Suppression of Thromboxane Receptor Gene Expression by Retinoids in Vascular Smooth Muscle Cells

et al. 2003

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Retinoic Acid–Induced Tissue Transglutaminase and Apoptosis in Vascular Smooth Muscle Cells

Cited by 53 publications

References 55 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

Retinoids and Pulmonary Hypertension

Transcription Suppression of Thromboxane Receptor Gene Expression by Retinoids in Vascular Smooth Muscle Cells

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