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, Masao; Wang, Hong; Hsieh, Chung Ming; Sibinga, Nicholas E.S.; Perrella, Mark A.; Lee, Mu En

doi:10.1074/jbc.272.35.22259

Cited by 50 publications

(35 citation statements)

References 48 publications

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“…Similarly, Djaborkhel et al reported that in lymphoma cells, TGF␤ impedes CREB1 and ATF2 from binding to the CRE site of the cyclin A promoter (9). However, in mink lung epithelial cells (Mv1Lu), the CREB-CRE interaction was found to be unaffected by TGF␤ (37). Although the exact cause of this discrepancy is unknown, one apparent difference between the present study and the one by Yoshizumi et al is the duration of TGF␤ treatment.…”

Section: Vol 27 2007 Creb-dependent Regulation Of Cyclin a 3495contrasting

confidence: 55%

Phosphorylation of the Cyclic AMP Response Element Binding Protein Mediates Transforming Growth Factor β-Induced Downregulation of Cyclin A in Vascular Smooth Muscle Cells

Kamiya

Sakakibara

Ryer

et al. 2007

Molecular and Cellular Biology

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Transforming growth factor ␤ (TGF␤), a multifunctional cytokine associated with vascular injury, is a potent inhibitor of cell proliferation. The current results demonstrate that the TGF␤-induced growth arrest of vascular smooth muscle cells (VSMCs) is associated with cyclin A downregulation. TGF␤ represses the cyclin A gene through a cyclic AMP (cAMP) response element, which complexes with the cAMP response element binding protein (CREB). The CREB-cyclin A promoter interaction is hindered by TGF␤, preceded by a TGF␤ receptor-dependent CREB phosphorylation. Induction of CREB phosphorylation with forskolin or 6bnz-cAMP mimics TGF␤'s inhibitory effect on cyclin A expression. Conversely, inhibition of CREB phosphorylation with a CREB mutant in which the phosphorylation site at serine 133 was changed to alanine (CREB-S133A) upregulated cyclin A gene expression. Furthermore, the CREB-S133A mutant abolished TGF␤-induced CREB phosphorylation, cyclin A downregulation, and growth inhibition. Since we have previously shown that the novel PKC isoform protein kinase C delta (PKC␦) is activated by TGF␤ in VSMCs, we tested the role of this kinase in CREB phosphorylation and cyclin A downregulation. Inhibition of PKC␦ by a dominant-negative mutant or by targeted gene deletion blocked TGF␤-induced CREB phosphorylation and cyclin A downregulation. Taken together, our data indicate that phosphorylation of CREB stimulated by TGF␤ is a critical step leading to the inhibition of cyclin A expression and, thus, VSMC proliferation.The stimulation of vascular smooth muscle cells (VSMCs) to proliferate following vascular injury is critical to the pathogenesis of both atherosclerosis and re-stenosis. Without such a stimulus, VSMCs are quiescent (nonproliferative) and transdifferentiated, evident by the high expression of contractile proteins. Following vascular injury or reconstruction, the vessel wall is exposed to chemical and mechanical stimuli, which lead to an active and dedifferentiated VSMC phenotype (23). Through mechanisms not fully understood, these activated VSMCs re-enter the cell cycle and engage in excessive cell division. This abnormal proliferation of VSMCs, along with enhanced migration and matrix protein production, leads to the formation of a highly cellular lesion (intimal hyperplasia) in atherosclerotic or re-stenotic vessels (23).In many ways, the pathogenesis of atherosclerosis and restenosis is similar to that of tumorigenesis; both involve excessive mitogenic responses and/or diminished growth inhibition. Among the known inhibitory growth factors, transforming growth factor ␤ (TGF␤), a member of a large family of a multipotent cytokines, induces cell cycle arrest in many cell types, including VSMCs (20,21). Furthermore, the loss of TGF␤-induced growth inhibition has been implicated in tumorigenesis (20). The acquisition of TGF␤ resistance found in several types of tumor cells is due to the inactivation of TGF␤ receptors or Smad genes (20). Despite the fact that TGF␤ is among the key cytokines implicated in the res...

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Section: Vol 27 2007 Creb-dependent Regulation Of Cyclin a 3495contrasting

confidence: 55%

Phosphorylation of the Cyclic AMP Response Element Binding Protein Mediates Transforming Growth Factor β-Induced Downregulation of Cyclin A in Vascular Smooth Muscle Cells

Kamiya

Sakakibara

Ryer

et al. 2007

Molecular and Cellular Biology

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“…In support of this assumption PP2A was reported to remove phosphate from serine-133 of CREB in HepG2 cells (40), and transforming growth factor ␤ was found to downregulate cyclin A by causing dephosphorylation of CRE binding proteins, a reaction which is counterbalanced by SV40 ST protein (42). On the other hand, peptide inhibitors of protein phosphatase 1 were found to increase phosphorylation of CREB in NIH 3T3 fibroblasts; in this study, SV40 ST antigen was found to have no effect on the phosphorylation status of CREB (2).…”

Section: Discussionmentioning

confidence: 71%

Transactivation of Murine Cyclin A by Polyomavirus Large and Small T Antigens

Schüchner

Nemethova

Belisova

et al. 2001

J Virol

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Polyomavirus large and small T antigens cooperate in the induction of S phase in serum-deprived Swiss 3T3 cells. While the large T antigen is able to induce S phase-specific enzymes, we have recently shown that both T antigens contribute to the production of the cyclins E and A and that the small T antigen is essential for the induction of cyclin A-dependent cdk2 activity (S. Schüchner and E. Wintersberger, J. Virol. 73:9266-9273, 1999). Here we present our attempts to elucidate the mechanisms by which the large and the small T antigens transactivate the murine cyclin A gene. Using Swiss 3T3 cells carrying the T antigens and various mutants thereof under the hormone-inducible mouse mammary tumor virus promoter, as well as transient-cotransfection experiments with the T antigens and cyclin A promoter-luciferase reporter constructs, we found the following. The large T antigen activates the cyclin A promoter via two transcription factor binding sites, a cyclic AMP responsive element (CRE), and the major negative regulatory site called CDE-CHR. While an intact binding site for pocket proteins is required for the function of this T antigen at the CDE-CHR, its activity at the CRE is largely independent thereof. In contrast, an intact J domain and an intact zinc finger are required at both sites. The small T antigen also appears to have an influence on the cyclin A promoter through the CRE as well as the CDE-CHR. For this an interaction with protein phosphatase 2A is essential; mutation of the J domain does not totally eliminate but greatly reduces the transactivating ability.The induction of S phase of the cell cycle is a complex reaction usually initiated at the cell surface through binding of ligands to receptors. Signal transduction pathways lead to the synthesis of S phase-specific enzymes and regulators, including the cyclins E and A. DNA tumor viruses require cells in S phase because they heavily depend on the cellular DNA synthesis machinery for the replication of their own DNA. Since they frequently infect differentiated cells, they have to interfere with the cellular mechanisms of growth regulation in order to drive cells out of the G 0 phase and into the S phase (reviewed in reference 19). This is accomplished by viral proteins which interact with various intermediates of the signal transduction pathway downstream of events taking place at the cell surface. One class of target for such viral proteins are the pocket proteins: pRB and its relatives p107 and p130. They negatively regulate members of the transcription factor family E2F (reviewed in reference 8). Adenovirus E1A, human papillomavirus (HPV) E7 protein, and the large T (LT) antigens of simian virus 40 (SV40), and polyomavirus (Py) bind to pocket proteins and cause a dissociation of the repressive complexes, which results in the transactivation of E2F responsive genes (19). Another region of the pleiotropic T antigens which is essential for this reaction is the J domain (reviewed in references 4 and 16), a sequence present in many chaperones capable ...

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“…For instance, at many promoters the YY1 protein activates transcriptional initiation by stimulating recruitment of RNA polymerase II while at other promoters YY1 represses transcription by sequestering CREB/ATF (95). Similarly, depending on context, the cyclin A gene has also been shown to be either up-or down-regulated through its upstream CREB/ATF site (15,16,92,93).…”

Section: Discussionmentioning

confidence: 99%

CREB/ATF-Dependent Repression of Cyclin A by Human T-Cell Leukemia Virus Type 1 Tax Protein

Kibler

Jeang

2001

J Virol

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Expression of the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax is correlated with cellular transformation contributing to the development of adult T-cell leukemia. Tax has been shown to modulate the activities of several cellular promoters. Existing evidence suggests that Tax need not directly bind to DNA to accomplish these effects but rather that it can act through binding to cellular factors, including members of the CREB/ATF family. Exact mechanisms of HTLV-1 transformation of cells have yet to be fully defined, but the process is likely to include both activation of cellular-growth-promoting factors and repression of cellular tumor-suppressing functions. While transcriptional activation has been well studied, transcriptional repression by Tax, reported recently from several studies, remains less well understood. Here, we show that Tax represses the TATA-less cyclin A promoter. Repression of the cyclin A promoter was seen in both ts13 adherent cells and Jurkat T lymphocytes. Two other TATA-less promoters, cyclin D3 and DNA polymerase ␣, were also found to be repressed by Tax. Interestingly, all three promoters share a common feature of at least one conserved upstream CREB/ATF binding site. In electrophoretic mobility shift assays, we observed that Tax altered the formation of a complex(es) at the cyclin A promoter-derived ATF site. Functionally, we correlated removal of the CREB/ATF site from the promoter with loss of repression by Tax. Furthermore, since a Tax mutant protein which binds CREB repressed the cyclin A promoter while another mutant protein which does not bind CREB did not, we propose that this Tax repression occurs through protein-protein contact with CREB/ATF.Infection with human T-cell leukemia virus type 1 (HTLV-1) has been linked to the development of several diseases: adult T-cell leukemia (ATL), tropical spastic paraparesis, and various neurological disorders termed HTLV-1-associated myelopathy (33). The HTLV-1-encoded oncoprotein Tax has been implicated in the transformation of T cells (reviewed in reference 91), as well as in tumor formation in transgenic mice (26). Although the precise mechanisms utilized by Tax to induce transformation are not known, this protein has been shown to modulate cellular genes that are involved in cellular proliferation and cell cycle control (reviewed in reference 55). Tax up-regulates expression of interleukin-2 (IL-2), IL-2 receptor, c-fos, c-Jun, erg-1, and granulocyte-macrophage colony-stimulating factor (reviewed in references 32 and 51; 52) and represses expression of the ␤-polymerase, c-myb, Lck, and p53 promoters (11,39,48,57,84). Tax has also been shown to affect the functions of IKK␥ (10, 27, 40), c-myc (69), Bax (8), MAD1 (41), cyclin D (56), and MyoD (63).Cyclins are critical factors in cell cycle progression (25,71,72). Cyclins associate with cyclin-dependent kinases and regulate the functions of cellular proteins that are required for progression through the cell cycle (G 1 , S, G 2 , and M) phases. The D cyclins are induced by ...

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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

Cited by 50 publications

References 48 publications

Phosphorylation of the Cyclic AMP Response Element Binding Protein Mediates Transforming Growth Factor β-Induced Downregulation of Cyclin A in Vascular Smooth Muscle Cells

Phosphorylation of the Cyclic AMP Response Element Binding Protein Mediates Transforming Growth Factor β-Induced Downregulation of Cyclin A in Vascular Smooth Muscle Cells

Transactivation of Murine Cyclin A by Polyomavirus Large and Small T Antigens

CREB/ATF-Dependent Repression of Cyclin A by Human T-Cell Leukemia Virus Type 1 Tax Protein

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