Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulation of intracellular cyclic adenosine monophosphate (cAMP) has been shown to inhibit the growth of cultured airway smooth-muscle cells, but the precise mechanism underlying the antimitogenic action of cAMP in these cells is unknown. We examined the effects of forskolin, an activator of adenylate cyclase, on DNA synthesis, cyclin D1 expression, and cAMP response element-binding protein (CREB) phosphorylation and DNA binding in bovine tracheal myocytes. DNA synthesis was assessed by measurement of [3H]thymidine incorporation. Cyclin D1 protein abundance and CREB phosphorylation were assessed by immunoblotting. Cyclin D1 promoter transcriptional activation was determined by measurement of luciferase activity in cells transiently cotransfected with complementary DNAs encoding the full-length cyclin D1 promoter subcloned into a luciferase reporter and beta-galactosidase (to normalize for transfection efficiency). The binding of nuclear proteins to the cyclin D1 promoter cAMP response element (CRE) was determined by electrophoretic mobility shift assay. We found that forskolin attenuated platelet-derived growth factor-induced DNA synthesis in a concentration-dependent manner. In addition, forskolin pretreatment decreased both cyclin D1 promoter activity and protein levels. Forskolin treatment induced the phosphorylation of CREB and increased the binding of nuclear protein to the cyclin D1 promoter CRE. Finally, addition of an antibody against CREB1 induced supershift of at least one protein-DNA complex. Together, these data suggest that cAMP suppresses cyclin D1 gene expression via phosphorylation and transactivation of CREB. Further studies are needed to determine whether this is the primary mechanism of cAMP-induced growth inhibition, or whether additional pathways are also involved.
Am J Respir Cell Mol Biol 1999 Feb
PMID:Forskolin inhibits cyclin D1 expression in cultured airway smooth-muscle cells. 992 28

Cyclin D1 (CD1) gene amplification is frequently observed in esophageal carcinosarcoma by differential polymerase chain reaction (DPCR). In this study, fluorescence in situ hybridization (FISH) was performed to show more direct evidence of CD1 gene amplification in patients with esophageal carcinosarcoma. FISH results were also compared with DPCR results studied previously. FISH analysis revealed CD1 gene amplification in all four patients with esophageal carcinosarcoma. CD1 gene amplification occurred with a high incidence in both components of esophageal carcinosarcoma, suggesting that CD1 gene amplification could have an important role in malignant transformation processes of esophageal carcinosarcoma. The results of the current study also suggest that FISH is a more sensitive method than DPCR. Because inactivation of p16 gene (which is a putative tumor suppressor gene) is thought to have similar oncogenic effects with CD1 gene amplification, DPCR was used to examine whether p16 homozygous deletion occurs in esophageal carcinosarcoma. These results suggest that homozygous deletion of the p16 gene occurs less frequently than CD1 gene amplification in esophageal carcinosarcoma. It does not seem to be an alternative event to CD1 gene amplification, though the number of studied cases was small.
Diagn Mol Pathol 1998 Oct
PMID:Cyclin D1 gene amplification and p16 gene deletion in patients with esophageal carcinosarcoma. 999 Apr 83

Cyclin D1 expression is jointly regulated by growth factors and cell adhesion to the extracellular matrix in many cell types. Growth factors are thought to regulate cyclin D1 expression because they stimulate sustained extracellular signal-regulated kinase (ERK) activity. However, we show here that growth factors induce transient ERK activity when added to suspended fibroblasts and sustained ERK activity only when added to adherent fibroblasts. Cell attachment to fibronectin or anti-alpha5beta1 integrin is sufficient to sustain the ERK signal and to induce cyclin D1 in growth factor-treated cells. Moreover, when we force the sustained activation of ERK, by conditional expression of a constitutively active MAP kinase/ERK kinase, we overcome the adhesion requirement for expression of cyclin D1. Thus, at least in part, fibroblasts are mitogen and anchorage dependent, because integrin action allows for a sustained ERK signal and the expression of cyclin D1 in growth factor-treated cells.
Mol Biol Cell 1999 Oct
PMID:Alpha5beta1 integrin controls cyclin D1 expression by sustaining mitogen-activated protein kinase activity in growth factor-treated cells. 1051 60

huCdc7 encodes a catalytic subunit for Saccharomyces cerevisae Cdc7-related kinase complex of human. ASK, whose expression is cell cycle-regulated, binds and activates huCdc7 kinase in a cell cycle-dependent manner (Kumagai, H., Sato, N., Yamada, M., Mahony, D. , Seghezzi, W., Lees, E., Arai, K., and Masai, H. (1999) Mol. Cell. Biol. 19, 5083-5095). We have expressed huCdc7 complexed with ASK regulatory subunit using the insect cell expression system. To facilitate purification of the kinase complex, glutathione S-transferase (GST) was fused to huCdc7 and GST-huCdc7-ASK complex was purified. GST-huCdc7 protein is inert as a kinase on its own, and phosphorylation absolutely depends on the presence of the ASK subunit. It autophosphorylates both subunits in vitro and phosphorylates a number of replication proteins to different extents. Among them, MCM2 protein, either in a free form or in a MCM2-4-6-7 complex, serves as an excellent substrate for huCdc7-ASK kinase complex in vitro. MCM4 and MCM6 are also phosphorylated by huCdc7 albeit to less extent. MCM2 and -4 in the MCM2-4-6-7 complex are phosphorylated by Cdks as well, and prior phosphorylation of the MCM2-4-6-7 complex by Cdks facilitates phosphorylation of MCM2 by huCdc7, suggesting collaboration between Cdks and Cdc7 in phosphorylation of MCM for initiation of S phase. huCdc7 and ASK proteins can also be phosphorylated by Cdks in vitro. Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks.
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PMID:Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial threonine residue of Cdc7 bY Cdks. 1084 77

Mantle cell lymphoma (MCL) has a worse prognosis than MALT lymphoma (MALTL). Distinction between MCL and MALTL on purely morphologic grounds can be difficult. Cyclin D1 (PRAD1/bcl1) is overexpressed in MCL as a result of a t(11:14) gene rearrangement, which leads to overexpression of cyclin D1 mRNA and protein. The immunohistochemical detection of cyclin D1 in MCL has been reported by several authors to be highly specific with sensitivity ranging from 70%-100%, but diagnostic laboratories have reported difficulty in finding a reliable method for cyclin D1 immunostaining. The aim of this study was to evaluate and optimize a method for detection of cyclin D1 by paraffin section immunoperoxidase staining. Sections of routinely processed tissue from five MCL and one splenic marginal zone lymphoma (MZL) were immunostained using a mixture of two primary monoclonal antibodies and a standard avidin-streptavidin method. Antigen retrieval was performed using 1) steam heat in citrate buffer, 2) as in "1" followed by sonication for one minute, and 3) as in "2" followed by enzymatic digestion. All the above were repeated, with the additional use of catalyzed signal amplification (CSA). Later, sections of the same cases, plus three MALTL were immunostained as in "2". Steam heat antigen retrieval alone produced the best results. All MCL showed positive nuclear staining while the MZL and all MALTL were negative. Sonication did not enhance staining noticeably, whereas enzymatic digestion produced cytoplasmic staining. CSA increased background staining with no significant gain in nuclear stain intensity. We conclude that cyclin D1 immunostaining of formalin-fixed, paraffin-embedded tissue can be reliably achieved by heat induces antigen retrieval and a cocktail of two monoclonal antibodies.
Appl Immunohistochem Mol Morphol 2000 Mar
PMID:Optimized cyclin D1 immunoperoxidase staining in mantle cell lymphoma. 1093 50

Cyclin D1 is a G1 cyclin that controls the transition of the cell cycle from G1 phase to S phase, and its gene is located on chromosome 11q13. We evaluated the expression of cyclin D1 mRNA in surgically resected specimens of gastric and colorectal cancers using quantitative RT-PCR. In this method, cDNA derived from cyclin D1 mRNA was amplified in a tube together with an internal control. The expression of cyclin D1 mRNA was high in 8 of 36 gastric cancer tissues (22%) and 9 of 27 (33%) colorectal cancer tissues, compared to normal mucosal tissues. In gastric cancers, the rate of cyclin D1 mRNA expression (an index of the density of DNA bands) was significantly higher in patients with tumors invading beyond the submucosal layer, regional lymph nodes and lymphatic vessels (i.e., patients with stage III or IV). In colorectal cancers, the rate of cyclin D1 mRNA expression was significantly higher in patients with venous invasion. Moreover, in patients with colorectal cancer, the survival rate of high-expression group was significantly lower than in low-expression group. Our results suggested that overexpression of cyclin D1 mRNA reflected the severity of gastric cancer and poor prognosis of colorectal cancer.
Res Commun Mol Pathol Pharmacol 1999
PMID:Evaluation of cyclin D1 mRNA expression in gastric and colorectal cancers. 1095 28

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-regulated nuclear receptor superfamily member. Liganded PPARgamma exerts diverse biological effects, promoting adipocyte differentiation, inhibiting tumor cellular proliferation, and regulating monocyte/macrophage and anti-inflammatory activities in vitro. In vivo studies with PPARgamma ligands showed enhancement of tumor growth, raising the possibility that reduced immune function and tumor surveillance may outweigh the direct inhibitory effects of PPARgamma ligands on cellular proliferation. Recent findings that PPARgamma ligands convey PPARgamma-independent activities through IkappaB kinase (IKK) raises important questions about the specific mechanisms through which PPARgamma ligands inhibit cellular proliferation. We investigated the mechanisms regulating the antiproliferative effect of PPARgamma. Herein PPARgamma, liganded by either natural (15d-PGJ(2) and PGD(2)) or synthetic ligands (BRL49653 and troglitazone), selectively inhibited expression of the cyclin D1 gene. The inhibition of S-phase entry and activity of the cyclin D1-dependent serine-threonine kinase (Cdk) by 15d-PGJ(2) was not observed in PPARgamma-deficient cells. Cyclin D1 overexpression reversed the S-phase inhibition by 15d-PGJ(2). Cyclin D1 repression was independent of IKK, as prostaglandins (PGs) which bound PPARgamma but lacked the IKK interactive cyclopentone ring carbonyl group repressed cyclin D1. Cyclin D1 repression by PPARgamma involved competition for limiting abundance of p300, directed through a c-Fos binding site of the cyclin D1 promoter. 15d-PGJ(2) enhanced recruitment of p300 to PPARgamma but reduced binding to c-Fos. The identification of distinct pathways through which eicosanoids regulate anti-inflammatory and antiproliferative effects may improve the utility of COX2 inhibitors.
Mol Cell Biol 2001 May
PMID:Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1. 1128 11

The role of regulators controlling the G1/S transition of the cell cycle was analyzed during neuronal apoptosis in post-mitotic cerebellar granule cells in an attempt to identify common mechanisms of control with transformed cells. Cyclin D1 and its associated kinase activity CDK4 (cyclin-dependent kinase 4) are major regulators of the G1/S transition. Whereas cyclin D1 is the regulatory subunit of the complex, CDK4 represents the catalytic domain that, once activated, will phosphorylate downstream targets such as the retinoblastoma protein, allowing cell-cycle progression. Apoptosis was induced in rat cerebellar granule cells by depleting potassium in presence of serum. Western-blot analyses were performed and protein kinase activities were measured. As apoptosis proceeded, loss in cell viability was coincident with a significant increase in cyclin D1 protein levels, whereas CDK4 expression remained essentially constant. Synchronized to cyclin D1 accumulation, cyclin-dependent kinase inhibitor p27Kip1 drastically dropped to 20% normal values. Cyclin D1/CDK4-dependent kinase activity increased early during apoptosis, reaching a maximum at 9-12 h and decreasing to very low levels by 48 h. Cyclin E, a major downstream target of cyclin D1, decreased concomitantly to the reduction in cyclin D1/CDK4-dependent kinase activity. We suggest that neuronal apoptosis takes place through functional alteration of proteins involved in the control of the G1/S transition of the cell cycle. Thus, apoptosis in post-mitotic neurons could result from a failed attempt to re-enter cell cycle in response to extracellular conditions affecting cell viability and it could involve mechanisms similar to those that promote proliferation in transformed cells.
J Mol Neurosci 2000 Dec
PMID:Potassium-induced apoptosis in rat cerebellar granule cells involves cell-cycle blockade at the G1/S transition. 1130 80

The androgen receptor (AR) is a ligand-regulated member of the nuclear receptor superfamily. The cyclin D1 gene product, which encodes the regulatory subunit of holoenzymes that phosphorylate the retinoblastoma protein (pRB), promotes cellular proliferation and inhibits cellular differentiation in several different cell types. Herein the cyclin D1 gene product inhibited ligand-induced AR- enhancer function through a pRB-independent mechanism requiring the cyclin D1 carboxyl terminus. The histone acetyltransferase activity of P/CAF (p300/CBP associated factor) rescued cyclin D1-mediated AR trans-repression. Cyclin D1 and the AR both bound to similar domains of P/CAF, and cyclin D1 displaced binding of the AR to P/CAF in vitro. These studies suggest cyclin D1 binding to the AR may repress ligand-dependent AR activity by directly competing for P/CAF binding.
Mol Endocrinol 2001 May
PMID:Cyclin D1 binds the androgen receptor and regulates hormone-dependent signaling in a p300/CBP-associated factor (P/CAF)-dependent manner. 1132 59

Adhesion to fibronectin through the alpha5beta1 integrin enables endothelial cells to proliferate in response to growth factors, whereas adhesion to laminin through alpha2beta1 results in growth arrest under the same conditions. On laminin, endothelial cells fail to translate Cyclin D1 mRNA and activate CDK4 and CDK6. Activated Rac, but not MEK1, PI-3K, or Akt, rescues biosynthesis of cyclin D1 and progression through the G(1) phase. Conversely, dominant negative Rac prevents these events on fibronectin. Mitogens promote activation of Rac on fibronectin but not laminin. This process is mediated by SOS and PI-3K and requires coordinate upstream signals through Shc and FAK. These results indicate that Rac is a crucial mediator of the integrin-specific control of cell cycle in endothelial cells.
Mol Cell 2001 Jul
PMID:Integrin-specific activation of Rac controls progression through the G(1) phase of the cell cycle. 1151 65


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