Disappearance of cyclin A correlates with permanent withdrawal of cardiomyocytes from the cell cycle in human and rat hearts.

Yoshizumi, Masao; Lee, Wen Sen; Hsieh, Chung Ming; Tsai, Jason; Li, Jian; Perrella, Mark A.; Patterson, Cam; Endege, Wilson O.; Schlegel, Robert; Lee, Mu En

doi:10.1172/jci117918

Cited by 99 publications

(83 citation statements)

References 61 publications

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“…32 P]dCTP-labeled, random primed APEG-1 cDNA probe as described (22,23). The hybridized filters were washed in 30 mM sodium chloride, 3 mM sodium citrate, and 0.1% SDS at 55°C and exposed to Kodak XAR film at Ϫ80°C.…”

Section: Methodsmentioning

confidence: 99%

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, a Novel Gene Preferentially Expressed in Aortic Smooth Muscle Cells, Is Down-regulated by Vascular Injury

Hsieh

Yoshizumi

Endege

et al. 1996

Journal of Biological Chemistry

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Despite the importance of phenotypic alterations in arterial smooth muscle cells (ASMC) during the pathogenesis of arteriosclerosis, little is known about genes that define differentiated ASMC. Using differential mRNA display, we isolated a novel gene preferentially expressed in the rat aorta and termed this gene APEG-1. The cDNA of rat APEG-1 contained an open reading frame encoding 113 amino acids, which would predict a basic protein of 12.7 kDa. The amino acid sequence of rat APEG-1 was highly conserved among human and mouse homologues (97 and 98%, respectively). Using an APEG-1 fusion protein containing an N-terminal c-Myc tag, we identified APEG-1 as a nuclear protein. By in situ hybridization, APEG-1 mRNA was expressed in rat ASMC. Although APEG-1 was expressed highly in differentiated ASMC in vivo, its expression was quickly down-regulated and disappeared in dedifferentiated ASMC in culture. In vivo, APEG-1 mRNA levels decreased by more than 80% in response to vascular injury as ASMC changed from a quiescent to a proliferative phenotype. Taken together, these data indicate that APEG-1 is a novel marker for differentiated ASMC and may have a role in regulating growth and differentiation of this cell type. Arterial smooth muscle cells (ASMC)1 constitute the major portion of the blood vessel wall, and their main function is to regulate vascular tone. By controlling vascular tone, ASMC have an important role in regulating blood pressure. Fully differentiated ASMC in normal vessel walls proliferate at an extremely low rate and express unique contractile proteins, ion channels, and signaling molecules required for their contractile function (1). In contrast to skeletal and cardiac muscle cells (2, 3), ASMC are not terminally differentiated in adult animals. In response to vascular injuries caused by smoking, hypercholesterolemia, hyperhomocystenemia, hypertension, or trauma (such as balloon angioplasty), ASMC dedifferentiate and change from a quiescent and contractile phenotype to a proliferative and synthetic phenotype (1, 4 -9). This proliferation of vascular smooth muscle cells is one of the most prominent features of arteriosclerosis, the leading cause of death in developed countries (4). Similar alterations in ASMC phenotypes occur during angiogenesis in solid tumors and may have an important role in determining the growth rate of these tumors (10 -12). Despite the importance of alteration of ASMC phenotypes in vascular diseases, little is known about molecular mechanisms regulating differentiation of this cell type (1). This is due, at least in part, to a lack of differentiation markers of ASMC.Several genes encoding proteins specific to smooth muscle cells, including smooth muscle ␣-actin, calponin, SM-22, and caldesmon, have been used as markers for differentiated smooth muscle cells (13-18). However, their expression is not limited to vascular smooth muscle cells. Recently, a homeobox gene gax has been shown to be highly expressed in vascular smooth muscle cells and may regulate their proliferation (19...

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Section: Methodsmentioning

confidence: 99%

“…RNA was fractionated on a 1.3% formaldehydeagarose gel and transferred to nitrocellulose filters. The filters were then hybridized with a [ 32 P]dCTP-labeled, random primed APEG-1 cDNA probe as described (22,23). The hybridized filters were washed in 30 mM sodium chloride, 3 mM sodium citrate, and 0.1% SDS at 55°C and exposed to Kodak XAR film at Ϫ80°C.…”

mentioning

confidence: 99%

, a Novel Gene Preferentially Expressed in Aortic Smooth Muscle Cells, Is Down-regulated by Vascular Injury

Hsieh

Yoshizumi

Endege

et al. 1996

Journal of Biological Chemistry

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“…Also, the activity of ATF-1 and CREB is regulated by their phosphorylation status (26). Although negative regulation of the cyclin A promoter during progression of the cell cycle could be mediated by the CDE/CHR site, we have shown elsewhere that down-regulation of cyclin A promoter activity during contact inhibition is mediated through the ATF site and that the abundance of ATF-1 protein and mRNA is reduced (21).…”

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confidence: 85%

“…The cyclin A ATF site is bound by ATF-1 and the cyclic AMP-responsive binding protein (CREB), which function as positive regulators of the cyclin A promoter (21,22,25). Also, the activity of ATF-1 and CREB is regulated by their phosphorylation status (26).…”

Section: Kip1mentioning

confidence: 99%

“…Although the transcription factors that bind to the CDE/ CHR site have not been cloned, these factors bind to the site only during the G 0 and the early G 1 phases of the cell cycle. The CDE/CHR-binding proteins may then repress the activity of the cyclin A activating transcription factor (ATF) site.The cyclin A ATF site is bound by ATF-1 and the cyclic AMP-responsive binding protein (CREB), which function as positive regulators of the cyclin A promoter (21,22,25). Also, the activity of ATF-1 and CREB is regulated by their phosphorylation status (26).…”

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Down-regulation of the Cyclin A Promoter by Transforming Growth Factor-β1 Is Associated with a Reduction in Phosphorylated Activating Transcription Factor-1 and Cyclic AMP-responsive Element-binding Protein

Yoshizumi

Wang

Hsieh

et al. 1997

Journal of Biological Chemistry

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Transforming growth factor (TGF)-␤1 prevents cell cycle progression by inhibiting several regulators, including cyclin A. To study the mechanisms by which TGF-␤1 down-regulates cyclin A gene expression, we transfected reporter plasmids driven by the cyclin A promoter into mink lung epithelial cells in the absence and presence of TGF-␤1. The TGF-␤1-induced down-regulation of cyclin A promoter activity appeared to be mediated via the activating transcription factor (ATF) site, because mutation of this site abolished down-regulation. Surprisingly, although TGF-␤1 treatment for 24 h markedly decreased cyclin A promoter activity, it did not decrease the abundance of the ATF-binding proteins ATF-1 and cyclic AMP-responsive binding protein (CREB). However, we detected 90 and 78% reductions (by Western analysis) in phosphorylated CREB and ATF-1, respectively, in mink lung epithelial cells treated with TGF-␤1. TGF-␤1-induced down-regulation of cyclin A promoter activity was reversed by okadaic acid (a phosphatase inhibitor) and by cotransfection with plasmids expressing the cAMP-dependent protein kinase catalytic subunit or the simian virus small tumor antigen (Sm-t, an inhibitor of PP2A). These data indicate that TGF-␤1 may down-regulate cyclin A promoter activity by decreasing phosphorylation of CREB and ATF-1. Transforming growth factor-␤ (TGF-␤)1 inhibits proliferation of most normal cell types in culture and in vivo (1, 2). Because TGF-␤ arrests progression of the cell cycle in mink lung epithelial (Mv1Lu) cells when added both early and late in the G 1 period (3), the inhibitory effect of TGF-␤ could be mediated by more than one mechanism. The progress of the cell cycle is regulated by the sequential expression of cyclins, followed by the activation of their associated cyclin-dependent kinases (Cdks) (4). Inhibitors of the Cdks block cell cycle progression (5-8). The many cell cycle regulators that TGF-␤ has been shown to affect include Cdk2, Cdk4, p15INK4b , p21 Waf1/Cip1 , p27 Kip1, and cyclin A (9 -17). Cyclin A associates with Cdk2 in the S phase of the cell cycle and with Cdc2 in the G 2 /M phase, and it is required for DNA replication in the S phase (4, 18). Cyclin A can also affect the G 1 /S transition, as overexpression of cyclin A but not cyclin D1 or E overcomes the G 1 /S block induced by loss of cell adhesion (19). The human and mouse cyclin A genes have been cloned recently and their promoters analyzed (20 -24), and the CDE/ CHR consensus sequence has been implicated as a negative regulator of cyclin A promoter activity during the cell cycle (20,23). Although the transcription factors that bind to the CDE/ CHR site have not been cloned, these factors bind to the site only during the G 0 and the early G 1 phases of the cell cycle. The CDE/CHR-binding proteins may then repress the activity of the cyclin A activating transcription factor (ATF) site.The cyclin A ATF site is bound by ATF-1 and the cyclic AMP-responsive binding protein (CREB), which function as positive regulators of the cyclin A promoter (...

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Expression of second messenger- and cyclin- dependent protein kinases during postnatal development of rat heart

1998

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During early postnatal development, cardiomyocytes, which comprise about 80% of ventricular mass and volume, become phenotypically developed to facilitate their contractile functions and terminally differentiated to grow only in size but not in cell number. These changes are due to the expression of contractile proteins as well as the regulation of intracellular signal transduction proteins. In this study, the expression patterns of several protein kinases involved in various cardiac functions and cell-cycle control were analyzed by Western blotting of ventricular extracts from 1-, 10-, 20-, 50-, and 365-day-old rats. The expression level of cAMP-dependent protein kinase was slightly decreased (20%) over the first year, whereas no change was detected in cGMP-dependent protein kinase I. Calmodulin-dependent protein kinase II, which is involved in Ca2+ uptake into the sarcoplasmic reticulum, was increased as much as ten-fold. To the contrary, the expressions of protein kinase C-alpha and iota declined 77% with age. Cyclin-dependent protein kinases (CDKs) such as CDK1, CDK2, CDK4, and CDK5, which are required for cell-cycle progression, abruptly declined to almost undetectable levels after 10-20 days of age. In contrast, other CDK-related kinases, such as CDK8 or Kkialre, did not change significantly or increased up to 50% with age, respectively. Protein kinases implicated in CDK regulation such as CDK7 and Wee1 were either slightly increased in expression or did not change significantly. All of the proteins that were detected in ventricular extracts were also identified in isolated cardiac myocytes in equivalent amounts and analyzed for their relative expression in ten other adult rat tissues.

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Disappearance of cyclin A correlates with permanent withdrawal of cardiomyocytes from the cell cycle in human and rat hearts.

Cited by 99 publications

References 61 publications

, a Novel Gene Preferentially Expressed in Aortic Smooth Muscle Cells, Is Down-regulated by Vascular Injury

, a Novel Gene Preferentially Expressed in Aortic Smooth Muscle Cells, Is Down-regulated by Vascular Injury

Down-regulation of the Cyclin A Promoter by Transforming Growth Factor-β1 Is Associated with a Reduction in Phosphorylated Activating Transcription Factor-1 and Cyclic AMP-responsive Element-binding Protein

Expression of second messenger- and cyclin- dependent protein kinases during postnatal development of rat heart

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