Role of the Adenomatous Polyposis Coli Gene Product in Human Cardiac Development and Disease

Rezvani, Mojgan; Liew, Choong‐Chin

doi:10.1074/jbc.m000870200

Cited by 21 publications

(22 citation statements)

References 27 publications

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“…The elevated GSK-3␤ activity leads to an increased degradation of ␤-catenin, which explains the lower ␤-catenin protein levels in the Dvl-1 Ϫ/Ϫ TAC group compared with wild-type littermates. Our results underscore the concept that ␤-catenin levels are regulated at the protein level rather than through control of its transcription, 26 because no correlation between ␤-catenin transcript numbers and protein levels was observed.…”

Section: Van De Schans Et Alsupporting

confidence: 57%

Interruption of Wnt Signaling Attenuates the Onset of Pressure Overload-Induced Cardiac Hypertrophy

et al. 2007

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Abstract-The hypertrophic response of the heart has been recognized recently as the net result of activation of prohypertrophic and antihypertrophic pathways. Here we report the involvement of the Wnt/Frizzled pathway in the onset of cardiac hypertrophy development. Stimulation of the Wnt/Frizzled pathway activates the disheveled (Dvl) protein. Disheveled subsequently can inhibit glycogen synthase kinase-3␤, a protein with potent antihypertrophic actions through diverse molecular mechanisms. In the Wnt/Frizzled pathway, inhibition of glycogen synthase kinase-3␤ leads to an increased amount of ␤-catenin, which can act as a transcription factor for several hypertrophy-associated target genes. In this study we subjected mice lacking the Dvl-1 gene and their wild-type littermates to thoracic aortic constriction for 7, 14, and 35 days. In mice lacking the Dvl-1 gene, 7 days of pressure overload-induced increases in left ventricular posterior wall thickness and expression of atrial natriuretic factor and brain natriuretic protein were attenuated compared with their wild-type littermates. ␤-Catenin protein amount was reduced in the group lacking the Dvl-1 gene, and an increased glycogen synthase kinase-3␤ activity was observed. Moreover, the increase in the amount of Ser 473 -phosphorylated Akt, a stimulator of cardiac hypertrophy, was lower in the group lacking the Dvl-1 gene.In conclusion, we have demonstrated that interruption of Wnt signaling in the mice lacking the Dvl-1 gene attenuates the onset of pressure overload-induced cardiac hypertrophy through mechanisms involving glycogen synthase kinase-3␤ and Akt. Therefore, the Wnt/Frizzled pathway may provide novel therapeutic targets for antihypertrophic therapy. Key Words: hypertrophy Ⅲ Wnt Ⅲ cell signaling Ⅲ glycogen synthase kinase-3␤ Ⅲ Akt C ardiac hypertrophy is an adaptive response of the heart to an increased workload, caused by a variety of pathological stimuli, including hypertension, myocardial infarction, and valvular disease. Because cardiomyocytes are terminally differentiated, these cells can only respond by hypertrophic growth. 1 This growth is initially beneficial but a sustained hypertrophic response often leads to heart failure. 2 In this hypertrophic response, extracellular stimulation is translated into a cellular response, leading to changes in the contractile apparatus and to an activation of many signaling pathways. 3 Several of these signaling pathways transduce prohypertrophic signals, but it has been shown that a number of endogenous molecules can regulate the hypertrophic response negatively. 4 One of the most powerful negative regulators that can antagonize the hypertrophic response is glycogen synthase kinase-3␤ (GSK-3␤), a ubiquitous serine/threonine protein kinase. 4,5 GSK-3␤ is a downstream regulatory switch of multiple signaling pathways that regulates a wide range of cellular functions. 6 Dysregulation of GSK-3␤ plays a role in many human diseases, including diabetes, Alzheimer's disease, bipolar disorder, cancer, 7 and heart failur...

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Section: Van De Schans Et Alsupporting

confidence: 57%

Interruption of Wnt Signaling Attenuates the Onset of Pressure Overload-Induced Cardiac Hypertrophy

et al. 2007

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“…However, the role of increased levels of APC and its association with apoptosis has not been reported in other cell types, indicating that the findings by Morin et al (Morin et al 1996) could have been a cell type specific phenomenon. In fact, apoptosis has been reported after the functional loss of APC by site-specific gene targeting in neuronal crest cells (Hasegawa et al 2000) or by antisense inhibition in cardiomyocytes (Rezvani and Liew 2000), further supporting our findings. In summary, our results provide a direction for future studies concerning the mechanisms by which APC plays a role in C 2 -ceramideinduced apoptosis in colon cancer cells.…”

Section: Discussionsupporting

confidence: 89%

Reduced levels of the adenomatous polyposis coli (APC) protein are associated with ceramide-induced apoptosis of colon cancer cells

Jaiswal

Narayan

2004

J Cancer Res Clin Oncol

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“…120 Preliminary results from our laboratory also indicate that ␤-adrenergic stimulation of neonatal rat cardiac myocytes upregulates the expression of ␤-catenin. 121 Because the ␤-catenin-LEF/TCF complex controls the activities of many genes mediating cell proliferation, it will be interesting to elucidate how ␤-catenin affects cardiac hypertrophy.…”

Section: Wnt Signaling In Postnatal Heartsmentioning

confidence: 69%

Glycogen Synthase Kinase-3β

Hardt¹,

Sadoshima²

2002

Circulation Research

355

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Abstract-Glycogen synthase kinase-3␤ (GSK-3␤) is a ubiquitously expressed constitutively active serine/threonine kinase that phosphorylates cellular substrates and thereby regulates a wide variety of cellular functions, including development, metabolism, gene transcription, protein translation, cytoskeletal organization, cell cycle regulation, and apoptosis. The activity of GSK-3␤ is negatively regulated by protein kinase B/Akt and by the Wnt signaling pathway. Increasing lines of evidence show that GSK-3␤ is an essential negative regulator of cardiac hypertrophy and that the inhibition of GSK-3␤ by hypertrophic stimuli is an important mechanism contributing to the development of cardiac hypertrophy. GSK-3␤ also plays an important role in regulating cardiac development. In this review, the role of GSK-3␤ in cardiac hypertrophy and development and the potential underlying mechanisms are discussed. Key Words: glycogen synthase kinase-3␤ Ⅲ hypertrophy Ⅲ development Ⅲ Akt Ⅲ Wnt pathway T he signaling mechanisms leading to cardiac hypertrophy have been intensively investigated over the past decade. 1-4 Identification of the signaling molecules necessary for the development of cardiac hypertrophy might lead to the development of therapeutic strategies to prevent or reverse the disease. During the past few years, mitogen-activated protein kinases (MAPKs), calcineurin (a Ca 2ϩ /calmodulindependent protein phosphatase), and Ca 2ϩ /calmodulindependent protein kinases have been intensively investigated because they positively regulate cardiac hypertrophy (see reviews 5,6 ). Equally important in exploring the signaling mechanisms promoting hypertrophy is the dissection of pathways counteracting these prohypertrophic signaling mechanisms, which thereby alleviates the hypertrophic responses. Accumulating evidence suggests that glycogen synthase kinase-3␤ (GSK-3␤) negatively regulates cardiac hypertrophy and that the inhibition of GSK-3␤ by hypertrophic stimuli is an important mechanism in the stimulation of cardiac hypertrophy. 7-12 GSK-3␤ also regulates cardiac development through its effect on Wnt signaling. In the present article, it is our goal to review recent findings regarding the role of GSK-3␤ in cardiac hypertrophy and development and to discuss the potential underlying mechanisms.

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Role of the Adenomatous Polyposis Coli Gene Product in Human Cardiac Development and Disease

Cited by 21 publications

References 27 publications

Interruption of Wnt Signaling Attenuates the Onset of Pressure Overload-Induced Cardiac Hypertrophy

Interruption of Wnt Signaling Attenuates the Onset of Pressure Overload-Induced Cardiac Hypertrophy

Reduced levels of the adenomatous polyposis coli (APC) protein are associated with ceramide-induced apoptosis of colon cancer cells

Glycogen Synthase Kinase-3β

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