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Query: UNIPROT:P06889 (Mol)
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Alveolar epithelial cells (AEC) proliferate during embryonic and fetal life, while in the adult lung AEC form a highly differentiated population that does not usually divide. Herein, we tested the hypothesis that differential expression of specific cell cycle control genes may occur during AEC development and transformation. We compared normal rat AEC in primary culture with transformed AEC for the expression of D-type G1 cyclins and cyclin-dependent protein kinases (cdc2 and cdk2). Cyclin D1 mRNA and protein were expressed at comparable levels in both normal rat AEC and in transformed AEC. In contrast, high levels of cyclin D2 mRNA and protein expression were only observed in normal 19-day fetal rat AEC and in transformed mink Mv1Lu cells derived from fetal mink lung epithelium. Moreover, treatment either with antisense oligodeoxynucleotides directed against cyclin D2 mRNA or with genistein (a tyrosine kinase inhibitor) caused significant inhibition of [3H]thymidine incorporation into DNA as well as inhibition of cyclin D2 expression in normal 19-day fetal rat AEC. p34cdc2 (but not p33cdk2 or p34cdk4) was expressed at progressively decreasing levels with corresponding histone H1 kinase activities during rat AEC development (19-day fetal > 21-day fetal > 13-day postnatal > adult rat AEC). The levels of p34cdc2 histone H1 kinase activity were significantly up-regulated or amplified in adult rat type 2 AEC following hyperoxic injury and repair and in transformed AEC. Collectively, these data support an important functional role for cyclin D2 and cdc2 genes in determining the proliferative versus nonproliferative phenotype of AEC during lung development, injury and repair, and transformation.
Am J Respir Cell Mol Biol 1995 Jan
PMID:Differential expression of cyclin D2 and cdc2 genes in proliferating and nonproliferating alveolar epithelial cells. 781 75

The cyclin D1 gene, located on chromosome 11q13, is frequently rearranged in parathyroid neoplasms and amplified in some carcinomas of other organs. Recent studies have detected amplification of cyclin D1 and other markers on chromosome 11q13 (evaluated by Southern or slot blot assays) in approximately 25-50% of squamous cell carcinomas of the esophagus and noted that amplification was associated with lessened survival time. We applied the technique of differential polymerase chain reaction to the evaluation of cyclin D1 gene amplification in squamous cell carcinomas of the esophagus. Cyclin D1 was found to be amplified in 10 of 45 (22%) primary tumors and three of 12 (25%) lymph node metastases. Lymph node metastases tended to be more common in patients with cyclin D1 amplification (70%) than in those without amplification (37%). In 36 patients with follow-up, cyclin D1 amplification was associated with decreased 1 year survival (28% vs. 59%). Cyclin D1 gene amplification in esophageal carcinomas can be evaluated by differential polymerase chain reaction and may provide useful prognostic information.
Diagn Mol Pathol 1994 Dec
PMID:Differential polymerase chain reaction assay of cyclin D1 gene amplification in esophageal carcinoma. 786 35

Cyclin D1, which is suggested to have a role in G1 control during the cell cycle, is genetically linked to BCL-1 and is widely overexpressed in parathyroid, breast, and squamous cancer cells. We postulated that cyclin D1 regulation may also be important in lung cancer. Therefore, we characterized the cell cycle-dependent expression of cyclin D1 at both mRNA and protein levels in synchronized human A549 lung carcinoma cells. Monospecific anti-cyclin D1 C-terminal peptide antibodies recognized both p36cyclinD1 and an as-yet uncharacterized 45 kD protein (p45). A549 cells were synchronized with well-studied drugs. Cyclin D1 mRNA expression remained relatively constant, with less than a twofold fluctuation during the cell cycle and with a minor peak at M phase. However, the p36cyclinD1 protein fluctuated during the A549 cell cycle and was expressed at very low levels in late G1 and at the G1/S boundary, but then increased in S phase and peaked at M phase. In contrast, p45 protein was expressed at relatively high levels in late G1 and reached maximal levels at the G1/S boundary, was expressed at decreased levels in S phase, and then had disappeared by M phase. Moreover, p45 was highly expressed only in transformed alveolar epithelial cells, but not in normal rat alveolar epithelial cells or fetal rat lung fibroblasts in primary cultures. In mink Mv1Lu cells, the expression of p45 was totally blocked by transforming growth factor-beta 1 treatment or contact inhibition. p45 protein was phosphorylated on serine, threonine, and tyrosine residues in A549 cells in culture. The phosphorylation of the p45 protein was cell cycle-regulated and reached its maximal levels at G2/M phase. The p45 protein had a different peptide map from p36cyclinD1 after cleavage with N-chlorosuccinimide. Immunoprecipitation studies showed that p45 was also anti-ubiquitin immunoreactive during the cell cycle. We conclude that p36cyclinD1 and the p45 protein are differentially regulated in a cell cycle-dependent manner in A549 cells. Although p45 is antigenically related to p36cyclinD1, it is probably not a closely cyclin-related protein. We speculate that p45 may be associated with malignant transformation and may play a distinct role from p36cyclinD1 in regulation of the cell cycle in A549 cells.
Am J Respir Cell Mol Biol 1994 Apr
PMID:Cell cycle-dependent expression of cyclin D1 and a 45 kD protein in human A549 lung carcinoma cells. 813 59

Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors. Recent studies suggested that high protein levels of cyclin D1 are not always produced when cyclin D1 mRNA is overexpressed in transfected cells, suggesting that posttranscriptional events may be important in cyclin D1 regulation. The mRNA cap-binding protein (eukaryotic initiation factor 4E [eIF-4E]) is a potential regulatory of several posttranscriptional events, and it can itself induce neoplastic transformation. Consequently, we examined eIF-4E as a potential regulator of cyclin D1. Overexpression of cyclin D1 mRNA in NIH 3T3 cells did not increase cyclin D1 protein. In contrast, overexpression of eIF-4E markedly increased the amount of cyclin D1 protein in NIH 3T3 cells. This increase was specific to cyclin D1 in comparison with the retinoblastoma gene product, c-Myc, actin, and eukaryotic initiation factor 2 alpha. We also examined cyclin D1 protein in cells expressing an estrogen receptor-Myc fusion protein because we previously found that eIF-4E increases after induction of c-myc function. In these cells, increased levels of eIF-4E protein were closely followed by increases in levels of cyclin D1 protein, but the level of cyclin D1 mRNA was not increased. We conclude that increases in cyclin D1 levels may result from increased expression of eIF-4E, and this regulation may be one determinant of cyclin D1 levels in the cell.
Mol Cell Biol 1993 Dec
PMID:Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. 824 56

Recent advances in defining the molecular mechanisms of cell cycle control in eukaryotes provide a basis for better understanding the hormonal control of cell proliferation in normal and neoplastic breast epithelium. It is now clear that a number of critical steps in cell cycle progression are controlled by families of serine/threonine kinases, the cdks. These kinases are activated by interactions with various cyclin gene products which form the regulatory subunits of the kinase complexes. Several families of cyclins control cell cycle progression in G1 phase, cyclins C, D and E, or in S, G2 and mitosis, cyclins A and B. Recent studies have defined the expression and regulation of cyclin genes in normal breast epithelial cells and in breast cancer cell lines. Following growth arrest of T-47D breast cancer cells by serum deprivation restimulation with insulin results in sequential induction of cyclin genes. Cyclin D1 mRNA increases within 1 h of mitogenic stimulation and is followed by increased expression of cyclins D3 and E in G1 phase, cyclin A in late G1/early S phase and cyclin B1 in G2. Similar results were observed following epidermal growth factor stimulation of normal breast epithelial cells. Other hormones--oestrogens and progestins--and growth factors--insulin-like growth factor-I and basic fibroblast growth factor--with actions in G1 were also investigated for their effects on G1 cyclin gene expression. In all cases there was an excellent correlation between the induction of cyclin D1 mRNA and subsequent entry into S phase. Furthermore, growth inhibition by antioestrogens and concurrent G1 arrest were preceded by an acute decrease in cyclin D1 gene expression. These observations suggest a likely role for cyclin D1 in mediating many of the known hormonal effects on cell proliferation in breast epithelial cells.
J Steroid Biochem Mol Biol 1993 Dec
PMID:Cyclin gene expression and growth control in normal and neoplastic human breast epithelium. 827 47

To define the mechanisms by which antiestrogens inhibit breast cancer cell proliferation, the effects of the antiestrogen ICI 182780 on G1 cyclins and their cyclin-dependent kinase (CDK) partners were investigated in MCF-7 cells. Inhibition of entry into S phase became evident 9 h after treatment, with the proportion of cells in S phase reaching a minimum by 24 h. ICI 182780 increased the proportion of the hypophosphorylated, growth inhibitory form of the retinoblastoma protein (pRB). This change began at 4-6 h, preceding effects on S phase. This suggests that there are early effects on the activities of CDKs that target pRB that are not merely a consequence of changes in cell cycle progression. The kinase activity of Cdk2 decreased to low levels at 18-24 h when changes in S phase and pRB phosphorylation were well advanced. An earlier effect was seen on kinase activity associated with immunoprecipitated cyclin D1, which was reduced approximately 40% by 12 h, with further decreases at 18-24 h. Cdk2 and Cdk4 protein levels remained constant over 24 h. Cyclin D1 messenger RNA and protein were down-regulated by ICI 182780 from 2 h, with levels halved at 8 h. ICI 182780 also increased the expression of the CDK inhibitors p27KIP1 and p21WAF1/CIP1 at later times. These observations are compatible with the hypothesis that antiestrogens block entry of cells into S phase and inhibit cell proliferation as the consequence of an early decline in pRB phosphorylation contributed to by reduced cyclin D1/Cdk4 activity. At later times, increased CDK inhibitor abundance may act to repress Cdk2 and Cdk4 activities, causing additional reductions in pRB phosphorylation, thus maintaining the antiestrogen blockade of cell cycle progression.
Mol Endocrinol 1995 Dec
PMID:Antiestrogen inhibition of cell cycle progression in breast cancer cells in associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. 861 16

Cyclin D1 controls G1-associated processes, including G0-to-G1 and G1-to-S transitions. This study demonstrates a novel aspect of cyclin D1 as a regulator of the transition between G1 and G0. Overexpression of cyclin D1 in MCF7 breast tumor cells resulted in a continued proliferation under low-serum conditions, whereas nonoverexpressing cells ceased to grow. This difference in growth was due to a reduced exit from G1 to G0 in cyclin D1-overexpressing cells. Our data therefore suggest a model in which cyclin D1 overexpression in tumor cells is responsible for hyperproliferation under growth factor-deprived conditions.
Mol Cell Biol 1996 Jun
PMID:Cyclin D1 triggers autonomous growth of breast cancer cells by governing cell cycle exit. 864 62

Cell cycle "checkpoints" help to ensure the integrity of normal cellular functions prior to replicative DNA synthesis and/or cell division. Cell kinetic abnormalities, particularly arrests at the G1/S and G2/M cell cycle checkpoints, are induced following exposure to ionizing radiation in vitro. Following irradiation, cellular signaling pathways may lead to G1 arrest and/or apoptosis at the G1/S cell cycle transition point. Transfection of cyclin D1, a G1/S cyclin, into a rat embryo cells (REC) results in cellular populations that overexpress cyclin D1, are transformed morphologically, demonstrate an increased incidence of apoptosis, and are tumorigenic in immune-deficient mice. Despite such phenotypic changes, transfected cell populations maintain the integrity of the G1 checkpoint following ionizing radiation. The transfected cells overexpressing Cyclin D1 have a statistically significant increase in the incidence of apoptosis as compared to parental REC strains or mock-transfected REC. The work provides further evidence of Cyclin D1 playing a critical role in maintaining the integrity of the G1/S checkpoint, via the activation of apoptotic pathways following exposure to ionizing radiation in vitro.
Somat Cell Mol Genet 1996 Mar
PMID:Cyclin D1 induced apoptosis maintains the integrity of the G1/S checkpoint following ionizing radiation irradiation. 878 92

Estrogens play a critical role in the etiology of found breast cancer. Estradiol promotes the growth of breast cancer cells in vivo and in vitro. Exogenous estrogens in both the environment and in the human diet increase the growth of breast cancer cells in vitro. A role for xenoestrogens in breast cancer etiology has been proposed but remains controversial. We examined the effects of the xenoestrogenic pesticide 1,1,1-trichloro-2,2-bis(chlorophenyl)ethane (DDT) on estrogen-receptor (ER)-positive MCF-7 and T-47D human breast cancer cells as well as on ER-negative HS 578Bst breast cancer cells and rat liver cells. Estradiol and DDT were found to increase the growth of MCF-7 cells in the presence of insulin. The activity of cyclin-dependent kinase (Cdk)2 increased in growth-arrested T-47D and MCF-7 cells treated with beta-estradiol or DDT. The steroidal antiestrogen ICI 182,780 prevented both growth and Cdk2 activation induced by estradiol or DDT. Increased phosphorylation of Cdk2 and the retinoblastoma protein (pRb1O5) was observed in ER-positive cells treated with DDT or estradiol. Cdk2 activity was not affected by DDT or estradiol in ER-negative HS 578Bst breast cancer cells or in rat liver epithelial cells. Cyclin D1 protein synthesis was increased by DDT and estradiol in MCF-7 cells. DDT and estradiol-induced ER-dependent transcriptional activation of estrogen response elements (EREs) in stably transfected MVLN cells, and ERE activation by low doses of DDT was increased by insulin. These findings suggest that DDT can stimulate breast cancer cells to enter into the cell cycle by directly affecting key regulatory elements. The relative potency of DDT in inducing cell-cycle progression appears to be only 100-300 times less than that of estradiol when measured in the presence of insulin. Therefore, the cancer risks associated with DDT exposure may be greater than first thought, especially when additional mitogenic stimuli are present.
Mol Carcinog 1997 Feb
PMID:DDT mimicks estradiol stimulation of breast cancer cells to enter the cell cycle. 904 86

D-type cyclins are involved in the regulation of the G1/S transition of the cell cycle in various cell types cultured in vitro. Little is, however, known about the expression pattern and functional role of D-type cyclins in physiological processes in vivo. In this report, we studied whether the expression of murine D-type cyclins correlates with the states of mouse uterine cell proliferation in vivo. Time-course changes in cyclin D1 and D3 mRNA levels in the uterine tissues of immature mice primed with 17 beta-estradiol (E2) were examined by Northern blot hybridization. c-fos and thymidine kinase (TK) mRNA levels were also examined as markers for the transition from G0 to G1 and the onset of S phase, respectively. Cyclin D1 and D3 mRNAs were induced 2.5-fold between c-fos and TK mRNA peaks. The E2-induced cyclin D1 and D3 gene expressions were blocked by antiestrogens tamoxifen and ICI 182,780. We also investigated the effects of cycloheximide (CHX), a protein synthesis inhibitor, on cyclin D1 and D3 gene expressions. When CHX was treated alone, cyclin D3, but not cyclin D1, mRNA was immediately superinduced. The E2-induced cyclin D3 gene expression was shifted by approximately 6 h when CHX was pretreated 1 hr before E2 administration. Interestingly, the 3H-thymidine incorporation experiment showed that the mouse uterine cell cycle progression also shifted by 6 hr with pretreatment of CHX. The overall results suggest that both cyclin D1 and D3 mRNAs are constitutively expressed in uterine tissues and induced by E2 at G1 phase of the mouse uterine cell cycle. However, the superinducibility and temporal shift of cyclin D3 by CHX suggest that there is a different regulatory mechanism underlying cyclin D1 and D3 gene expressions in the mouse uterine cell cycle progression.
Mol Reprod Dev 1997 Apr
PMID:Estrogen-induced cyclin D1 and D3 gene expressions during mouse uterine cell proliferation in vivo: differential induction mechanism of cyclin D1 and D3. 909 91


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