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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogens are potent mitogens in a number of target tissues including the mammary gland where they play a pivotal role in the development and progression of mammary carcinoma. The demonstration that estrogen-induced mitogenesis is associated with the recruitment of non-cycling, G0, cells into the cell cycle and an increased rate of progression through G1 phase, has focused attention on the estrogenic regulation of molecules with a known role in the control of G1-S phase progression. These experiments provide compelling evidence that estrogens regulate the expression and function of c-Myc and cyclin D1 and activate cyclin E-Cdk2 complexes, all of which are rate limiting for progression from G1 to S phase. Furthermore, these studies reveal a novel mechanism of activation of cyclin E-Cdk2 complexes whereby estrogens promote the formation of high molecular weight complexes lacking the CDK inhibitor p21. Inducible expression of either c-Myc or cyclin D1 can mimic the effects of estrogen in activating the cyclin E-Cdk2 complexes and promoting S phase entry, providing evidence for distinct c-Myc and cyclin D1 pathways in estrogen-induced mitogenesis which converge on the activation of cyclin E-Cdk2. These data provide new mechanistic insights into the known mitogenic effects of estrogens and identify potential downstream targets that contribute to their role in oncogenesis.
J Steroid Biochem Mol Biol 1998 Apr
PMID:Estrogen regulation of cell cycle progression in breast cancer cells. 969 70

Loss-of-function mutations of p16(INK4a) have been identified in a large number of human tumors. An established biochemical function of p16 is its ability to specifically inhibit cyclin D-dependent kinases in vitro, and this inhibition is believed to be the cause of the p16-mediated G1 cell cycle arrest after reintroduction of p16 into p16-deficient tumor cells. However, a mutant of Cdk4, Cdk4(N158), designed to specifically inhibit cyclin D-dependent kinases through dominant negative interference, was unable to arrest the cell cycle of the same cells (S. van den Heuvel and E. Harlow, Science 262:2050-2054, 1993). In this study, we determined functional differences between p16 and Cdk4(N158). We show that p16 and Cdk4(N158) inhibit the kinase activity of cellular cyclin D1 complexes through different mechanisms. p16 dissociated cyclin D1-Cdk4 complexes with the release of bound p27(KIP1), while Cdk4(N158) formed complexes with cyclin D1 and p27. In cells induced to overexpress p16, a higher portion of cellular p27 formed complexes with cyclin E-Cdk2, and Cdk2-associated kinase activities were correspondingly inhibited. Cells engineered to express moderately elevated levels of cyclin E became resistant to p16-mediated growth suppression. These results demonstrate that inhibition of cyclin D-dependent kinase activity may not be sufficient to cause G1 arrest in actively proliferating tumor cells. Inhibition of cyclin E-dependent kinases is required in p16-mediated growth suppression.
Mol Cell Biol 1998 Sep
PMID:Requirement of cyclin E-Cdk2 inhibition in p16(INK4a)-mediated growth suppression. 971 Jun 13

The retinoblastoma (pRB) family of proteins includes three proteins known to suppress growth of mammalian cells. Previously we had found that growth suppression by two of these proteins, p107 and p130, could result from the inhibition of associated cyclin-dependent kinases (cdks). One important unresolved issue, however, is the mechanism through which inhibition occurs. Here we present in vivo and in vitro evidence to suggest that p107 is a bona fide inhibitor of both cyclin A-cdk2 and cyclin E-cdk2 that exhibits an inhibitory constant (Ki) comparable to that of the cdk inhibitor p21/WAF1. In contrast, pRB is unable to inhibit cdks. Further reminiscent of p21, a second cyclin-binding site was mapped to the amino-terminal portions of p107 and p130. This amino-terminal domain is capable of inhibiting cyclin-cdk2 complexes, although it is not a potent substrate for these kinases. In contrast, a carboxy-terminal fragment of p107 that contains the previously identified cyclin-binding domain serves as an excellent kinase substrate although it is unable to inhibit either kinase. Clustered point mutations suggest that the amino-terminal domain is functionally important for cyclin binding and growth suppression. Moreover, peptides spanning the cyclin-binding region are capable of interfering with p107 binding to cyclin-cdk2 complexes and kinase inhibition. Our ability to distinguish between p107 and p130 as inhibitors rather than simple substrates suggests that these proteins may represent true inhibitors of cdks.
Mol Cell Biol 1998 Sep
PMID:Dual cyclin-binding domains are required for p107 to function as a kinase inhibitor. 971 Jun 22

Prolinedithiocarbamate (PDTC) and diethyldithiocarbamate (DDTC) are cancer chemopreventive agents and can be biotransformed to prolinethiuramdisulfide (PTDS) and tetraethylthiuramdisulfide (disulfiram; DTDS), respectively. We found that the reactive metabolites PTDS and DTDS induced apoptosis after G1/S arrest. Phosphorylation of cyclin E, inhibition of cyclin-dependent kinase 2 activity, and degradation of cyclin E were found in human hepatoma Hep G2 cells during apoptosis. Moreover, PTDS and DTDS decreased the level of bcl-2 but increased the level of p53. In contrast, PDTC, DDTC, and ammonium dithiocarbamate (ADTC) did not induce apoptosis; rather they led to the induction of p53 and p21 followed by G1/S arrest. PDTC, DDTC, and ADTC also arrested cells in G1 phase. We then examined the effects of PTDS and DTDS on the signal transduction mechanisms leading to apoptosis. Although the transcription factors NFkappaB and AP-1 cooperatively decreased their DNA-binding activities to kappaB and 12-O-tetradecanoylphorbol-13-acetate-responsive elements, respectively, and p53 increased DNA-binding activity in the early stage but decreased it in the latter stage after treatment with PTDS, when the human Hep G2 cells were undergoing apoptosis. In summary, our results indicated that (i) PTDS and DTDS induced apoptosis and G1/S arrest mediated by p53, whereas PDTC, DDTC, and ADTC induced p53-dependent p21 expression leading to G1/S arrest; (ii) PDTC, DDTC, and ADTC induced p21/KIP1/CIP1 expression in a p53-dependent pathway leading to G1/S arrest; and (iii) NFkappaB, AP-1, and bcl-2 were downregulated during PTDS- and DTDS-induced apoptosis. These results suggested that PTDS and DTDS induced p53-dependent apoptosis, whereas PDTC, DDTC, and ADTC induced G1/S arrest. Apoptosis is regulated by the modulation of intracellular effectors such as NFkappaB, AP-1, and bcl-2 and activation of p53 in early stages.
Mol Carcinog 1998 Aug
PMID:Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFkappaB, c-fos/c-jun, and p53 proteins. 972 16

NF-kappa B/Rel family plays a pivotal role in a wide variety of cellular functions including growth, development, apoptosis and stress responses. Recent studies indicated that NF-kappa B is also involved in the cell cycle regulation, and high expression of c-Rel results in a cell cycle arrest at the G1/S-phase transition (Bash, J., Zong, W,-X., and Gelinas, C. (1997) Mol. Cell. Biol. 17, 6526-6536). Here we report the detection of Cdk2, a critical kinase responsible for the G1/S-phase transition, in immune complexes precipitated by the NF-kappa B antisera. Cdk2 and NF-kappa B association was detected by co-precipitation in the nuclear lysates of the G1/S-phase cells, and was found in cultured cell lines and in T cells purified from human peripheral blood. Using an affinity column containing the C-terminal peptide of human c-Rel, we isolated cyclin E, the regulatory subunit of the Cdk2 complex, as a c-Rel-binding protein. These findings support and provide physical basis for the involvement of NF-kappa B in the G1/S-phase cell cycle control, and suggest an important role played by the C-terminal sequence of c-Rel.
 ...
PMID:Association of Cdk2/cyclin E and NF-kappa B complexes at G1/S phase. 973 Dec 6

Using a new inducible form of phosphatidylinositol 3-kinase (PI 3-kinase) we have found that PI 3-kinase activation has the following effects on cell growth and proliferation. (i) Activation of PI 3-kinase was sufficient to promote entry into S phase of the cell cycle within several hours. This was shown by activation of cyclin-dependent kinase 4 (Cdk4) and Cdk2 and by the induction of DNA synthesis. (ii) PI 3-kinase activation alone was not, however, sufficient to provide for progression through the entire cell cycle. Instead, prolonged activation of PI 3-kinase in the absence of serum stimulation resulted in apoptosis. It is possible that the cells undergo apoptosis because the PI 3-kinase-induced entry into the cell cycle is abnormal. For example, we found that the cyclin E-Cdk2 complex, which normally disappears after entry into S phase of the cell cycle, fails to be downregulated following induction by PI 3-kinase. (iii) Finally, we found that prolonged activation of PI 3-kinase in the presence of serum resulted in cellular changes that resemble those associated with oncogenic transformation. The cells reached high densities, were irregular and refractile in appearance, and formed colonies in soft agar. In contrast, neither PI 3-kinase nor serum stimulation alone could induce these changes. Our results suggest that activation of PI 3-kinase promotes anchorage-independent cell growth and entry into the cell cycle but does not abrogate the growth factor requirement for cell proliferation.
Mol Cell Biol 1998 Oct
PMID:Activation of phosphatidylinositol 3-kinase is sufficient for cell cycle entry and promotes cellular changes characteristic of oncogenic transformation. 974 87

We earlier reported that TIS21 mRNA expression was markedly decreased in A549 and NCIH69 human lung cancer cells and in thymic carcinoma tissues obtained from transgenic mice containing simian virus 40 large T antigen (J Cancer Res Clin Oncol 121:279-284, 1995). To determine how TIS21 inhibits growth, we made 293 cells that constitutively expressed TIS21 protein. The constitutive TIS21 expresser lines C9 and C11 grew to a lower saturation density than did those in the vector-transfected clones (V7 and V10) and antisense-transfected clones (AS1 and AS4), and the size of the C9 and C11 cells increased significantly after transfection with TIS21 cDNA. The serum-stimulated cell cycle was analyzed by fluorescence-activated cell sorting after double thymidine treatment; V10 progressed normally through the cell division cycle, but C9 and C11 cells accumulated continuously in G1 phase until 36 h after treatment. On the other hand, the progression of cells that had already entered to S or G2/M phase was not inhibited. When cell-cycle regulatory proteins were measured, C9 and C11 cells showed significantly reduced synthesis of cyclin E and cyclin-dependent kinase (cdk) 4 as well as a decrease in cyclin E-associated cdk activity. These observations led us to conclude that TIS21 overexpression in G1 phase decreased the amounts of cyclin E and cdk4, thereby decreasing the activity of cdks at the G1-S transition.
Mol Carcinog 1998 Sep
PMID:Induction of growth inhibition of 293 cells by downregulation of the cyclin E and cyclin-dependent kinase 4 proteins due to overexpression of TIS21. 976 35

The E2F transcription factors are essential regulators of cell growth in multicellular organisms, controlling the expression of a number of genes whose products are involved in DNA replication and cell proliferation. In Saccharomyces cerevisiae, the MBF and SBF transcription complexes have functions similar to those of E2F proteins in higher eukaryotes, by regulating the timed expression of genes implicated in cell cycle progression and DNA synthesis. The CDC6 gene is a target for MBF and SBF-regulated transcription. S. cerevisiae Cdc6p induces the formation of the prereplication complex and is essential for initiation of DNA replication. Interestingly, the Cdc6p homolog in Schizosaccharomyces pombe, Cdc18p, is regulated by DSC1, the S. pombe homolog of MBF. By cloning the promoter for the human homolog of Cdc6p and Cdc18p, we demonstrate here that the cell cycle-regulated transcription of this gene is dependent on E2F. In vivo footprinting data demonstrate that the identified E2F sites are occupied in resting cells and in exponentially growing cells, suggesting that E2F is responsible for downregulating the promoter in early phases of the cell cycle and the subsequent upregulation when cells enter S phase. Our data also demonstrate that the human CDC6 protein (hCDC6) is essential and limiting for DNA synthesis, since microinjection of an anti-CDC6 rabbit antiserum blocks DNA synthesis and CDC6 cooperates with cyclin E to induce entry into S phase in cotransfection experiments. Furthermore, E2F is sufficient to induce expression of the endogenous CDC6 gene even in the absence of de novo protein synthesis. In conclusion, our results provide a direct link between regulated progression through G1 controlled by the pRB pathway and the expression of proteins essential for the initiation of DNA replication.
Mol Cell Biol 1998 Nov
PMID:Cell cycle-regulated expression of mammalian CDC6 is dependent on E2F. 977 82

A cyclin-dependent kinase (cdk) inhibitor, p27Kip1 (p27), binds to the cyclin E-cdk2 complex and functions as a suppressor of cell cycle promotion. Here, the involvement of p27 in the growth of normal human endometrium was immunohistochemically studied, and the findings were compared with those of Ki-67, cyclin E and cdk2. In addition, to elucidate the effect of progesterone on the expression of p27, tissues from patients with endometrial hyperplasia were examined before and after the administration of medroxyprogesterone acetate (MPA) for the treatment of this disease. In the glandular cells of the normal endometrium, p27 was negligible during the proliferative phase, whereas it was markedly increased in the secretory phase. The staining pattern of Ki-67 was the reverse. Cyclin E/cdk2-positive cells were observed throughout the menstrual cycle. In the secretory phase, the cyclin E/cdk2-positive cells were also positive for p27, suggesting an interaction between these molecules. Stromal cells, especially in the basalis, showed a consistent expression of p27 throughout the menstrual cycle. The expression of p27 in hyperplastic epithelia before the MPA treatment was negligible, whereas it was greatly increased after the treatment. The Ki-67 positivity decreased after the treatment. These findings suggest that p27 is involved in the progesterone-induced growth suppression of normal and hyperplastic endometria.
Mol Hum Reprod 1998 Sep
PMID:Involvement of cyclin-dependent kinase inhibitor p27Kip1 in growth inhibition of endometrium in the secretory phase and of hyperplastic endometrium treated with progesterone. 978 52

Cyclin E, a partner of the cyclin-dependent kinase Cdk2, has been implicated in positive control of the G1/S phase transition. Whereas degradation of cyclin E has been shown to be exquisitely regulated by ubiquitination and proteasomal action, little is known about posttranscriptional aspects of its biogenesis. In a yeast-based screen designed to identify human proteins that interact with human cyclin E, we identified components of the eukaryotic cytosolic chaperonin CCT. We found that the endogenous CCT complex in yeast was essential for the maturation of cyclin E in vivo. Under conditions of impaired CCT function, cyclin E failed to accumulate. Furthermore, newly translated cyclin E, both in vitro in reticulocyte lysate and in vivo in human cells in culture, is efficiently bound and processed by the CCT. In vitro, in the presence of ATP, the bound protein is folded and released in order to become associated with Cdk2. Thus, both the acquisition of the native state and turnover of cyclin E involve ATP-dependent processes mediated by large oligomeric assemblies.
Mol Cell Biol 1998 Dec
PMID:Maturation of human cyclin E requires the function of eukaryotic chaperonin CCT. 981 44


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