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

The presence of two families of seven distinct mammalian cyclin-dependent kinase (CDK) inhibitor genes is thought to mediate the complexity of connecting a variety of cellular processes to the cell cycle control pathway. The distinct pattern of tissue expression of CDK inhibitor genes suggests that they may function as tumor suppressors with different tissue specificities. To test this hypothesis, we have characterized two strains of double mutant mice lacking either p18(INK4c) and p27(KIP1) or p18(INK4c) and p21(CIP1/WAF1). Loss of both p18 and p27 function resulted in the spontaneous development by 3 months of age of at least eight different types of hyperplastic tissues and/or tumors in the pituitary, adrenals, thyroid, parathyroid, testes, pancreas, duodenum, and stomach. Six of these hyperplastic tissues and tumors were in endocrine organs, and several types of tumors routinely developed within the same animal, a phenotype reminiscent of that seen in combined human multiple endocrine neoplasia syndromes. The p18-p21 double null mice, on the other hand, developed pituitary adenomas, multifocal gastric neuroendocrine hyperplasia, and lung bronchioalveolar tumors later in life. G(1) CDK2 and CDK4 kinase activities were increased in both normal and neoplastic tissues derived from mice lacking individual CDK inhibitors and were synergistically stimulated by the simultaneous loss of two CDK inhibitors. This indicates that an increase in G(1) CDK kinase activity is a critical step during but is not sufficient for tumor growth. Our results suggest that functional collaborations between distinct CDK inhibitor genes are tissue specific and confer yet another level of regulation in cell growth control and tumor suppression.
Mol Cell Biol 2000 Aug
PMID:Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. 1091 96

Cyclin-dependent kinase inhibitors (CDKI) are negative regulators of cell cycle progression by binding the cyclin-CDK complex and inhibiting the CDK activity. Genetic alteration in the CDKI genes has been implicated for carcinogenesis. To test the genetic alteration in the p27 and p57 genes, KIP family CDKI genes, 30 gastric tumor-normal pairs and 8 gastric cancer cell lines were analyzed for mutations by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP). No mutation was detected in these genes although length polymorphisms in the proline-alanine repeat of the p57 gene were detected. When the p27 and p57 mRNAs were analyzed in gastric cancer cell lines by RT-PCR, the p27 mRNA was expressed considerably high in tumor cells but expression of the p57 mRNA was much low in gastric cancer cell lines compared to that of normal cells. The result suggests that inactivation of gene expression rather than mutations in the p57 gene accounts possibly for the involvement of this gene in tumorigenesis of gastric cancer. However, expression of the p27 gene seems to be essential for cell survival.
Exp Mol Med 2000 Jun 30
PMID:Mutation and expression of the p27KIP1 and p57KIP2 genes in human gastric cancer. 1092 19

Murine myoblast cell lines stably transfected with expression vectors containing homeobox Msx1 cDNA in sense (F31-c) or antisense (F3R1) orientation have contrasting phenotypes. F3R1 cells readily differentiate in medium containing low serum whereas F31-c cells fail to differentiate under these conditions. The mechanism by which exogenous overexpression of Msx1 leads to the altered phenotype of F31-c cells and the downstream targets of Msx1 are unknown. Using the method of differential display, we have identified four cDNAs that represent transcripts up-regulated in F31-c. Two of these cDNAs are homologous to ribosomal proteins S23 and S24 while the third has homology to sequences in the murine Tcp-1 gene. A fourth cDNA does not have appreciable homology to cDNA sequences deposited in the NIH GenBank. Since withdrawal from the cell cycle and enhanced expression of MyoD commonly precede differentiation of myoblasts into myotubes, we also examined regulation of the major cell cycle proteins as well as MyoD by Western blot analysis. We show that the levels of Cdks 2, 4 and 6, cyclins A and D, and the Cdk inhibitor p27 in both proliferating and serum-starved F31-c cells were similar to those in F3R1. Finally, although MyoD protein levels increased in both cell types after 72 h incubation in serum depleted medium, the levels of MyoD in serum-starved F31-c cells were 2-4 fold lower. We postulate that the reduced amount of MyoD is sufficient to permit reversible withdrawal of F31-c cells from the cell cycle, but is inadequate to permit myogenesis.
Mol Cell Biochem 2000 May
PMID:Exogenous expression of Msx1 renders myoblasts refractory to differentiation into myotubes and elicits enhanced biosynthesis of four unique mRNAs. 1093 29

We describe here that DE1-adenovirus vectors (AV) expressing a p27-p16 fusion molecule, termed W9, induce tumor cell apoptosis when overexpressed in a wide range of tumor cell types. However, in primary human cells derived from a variety of normal tissues, AV-W9 induced minimal apoptosis. In tumor cells AV-W9 demonstrated 5- to 50-fold greater tumoricidal activity than either of the parental molecules p16 and p27. In these studies, AV-W9 elicited apoptosis independent of the p53 and Rb status of the tumor cells. In several murine tumor models AV-W9 demonstrated p53-independent antitumor activity. It completely prevented tumor formation in two ex vivo models, whereas the parental molecules resulted in partial protection. Furthermore, AV-W9 induced tumor regression or suppressed tumor growth when introduced intratumorally into preestablished tumors in mice. This effect may be mediated through tumor cell apoptosis or antiangiogenic activity of AV-W9. Thus, this novel chimeric molecule is more potent and capable of killing a broader spectrum of tumors than the parental p16 and p27 molecules independent of the tumor cell p53 and phenotype and represents a powerful new therapeutic agent for cancer gene therapy.
Mol Ther 2000 Aug
PMID:The p53-independent tumoricidal activity of an adenoviral vector encoding a p27-p16 fusion tumor suppressor gene. 1094 44

Fibroblast proliferation and extracellular matrix accumulation characterize idiopathic pulmonary fibrosis (IPF). We evaluated the presence of tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4; collagenase-1, -2, and -3; gelatinases A and B; and membrane type 1 matrix metalloproteinase (MMP) in 12 IPF and 6 control lungs. TIMP-1 was found in interstitial macrophages and TIMP-2 in fibroblast foci. TIMP-3 revealed an intense staining mainly decorating the elastic lamina in vessels. TIMP-4 was expressed in IPF lungs by epithelial and plasma cells. TIMP-2 colocalized with Ki67 in fibroblasts, whereas TIMP-3 colocalized with p27 in inflammatory and epithelial cells. Collagenase-1 was localized in macrophages and alveolar epithelial cells, collagenase-2 was localized in a few neutrophils, and collagenase-3 was not detected. MMP-9 was found in neutrophils and subepithelial myofibroblasts. Myofibroblast expression of MMP-9 was corroborated in vitro by RT-PCR. MMP-2 was noticed in myofibroblasts, some of them close to areas of basement membrane disruption, and membrane type 1 MMP was noticed in interstitial macrophages. These findings suggest that in IPF there is higher expression of TIMPs compared with collagenases, supporting the hypothesis that a nondegrading fibrillar collagen microenvironment is prevailing.
Am J Physiol Lung Cell Mol Physiol 2000 Sep
PMID:TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? 1095 32

Irreversible G(1) arrest in senescent human fibroblasts is mediated by two inhibitors of cyclin-dependent kinases (Cdks), p21(Cip1/SDI1/WAF1) and p16(Ink4A). To determine the physiological and molecular events that specifically require p21, we studied senescence in human diploid fibroblasts expressing the human papillomavirus type 16 E6 oncogene, which confers low p21 levels via enhanced p53 degradation. We show that in late-passage E6 cells, high Cdk activity drives the cell cycle, but population expansion is slowed down by crisis-like events, probably owing to defective cell cycle checkpoints. At the end of lifespan, terminal-passage E6 cells exhibited several aspects of the senescent phenotype and accumulated unphosphorylated pRb and p16. However, both replication and cyclin-Cdk2 kinase activity were still not blocked, demonstrating that phenotypic and replicative senescence are uncoupled in the absence of normal p21 levels. At this stage, E6 cells also failed to upregulate p27 and inactivate cyclin-Cdk complexes in response to serum deprivation. Eventually, irreversible G(1) arrest occurred coincident with inactivation of cyclin E-Cdk2 owing to association with p21. Similarly, when p21(-/-) mouse embryo fibroblasts reached the end of their lifespan, they had the appearance of senescent cells yet, in contrast to their wild-type counterparts, they were deficient in downregulating bromodeoxyuridine incorporation, cyclin E- and cyclin A-Cdk2 activity, and inhibiting pRb hyperphosphorylation. These data support the model that the critical event ensuring G(1) arrest in senescence is p21-dependent Cdk inactivation, while other aspects of senescent phenotype appear to occur independently of p21.
Mol Cell Biol 2000 Sep
PMID:Uncoupling between phenotypic senescence and cell cycle arrest in aging p21-deficient fibroblasts. 1095 72

PCR targeting the IS 6110 has been considered specific for identification of Mycobacterium tuberculosis and is frequently applied to confirm the presence of this organism directly in biological specimens. However, several authors found that some M. tuberculosis strains failed to hybridize with the IS 6110 probe and other authors found that false-positive results may be obtained for clinical samples when some methods based on IS 6110 are used. In the present study, the p27 gene isolated from a cosmid library was found to be highly specific for M. tuberculosis complex strains and allowed us to develop a PCR-based assay for rapid detection and identification of this mycobacterium. One pair of primers and two oligonucleotide probes were successfully used to amplify and to detect the DNA of strains belonging to the M. tuberculosis complex. These primers and probes did not hybridize with DNA from any of the 21 other mycobacterial species tested. It is worth noting that the chosen primers and probes hybridize with DNA from the M. tuberculosis strain with no IS 6110, furthermore no strain without p27 was found among the 410 strains tested in the present study.
Mol Cell Probes 2000 Aug
PMID:Cloning of a gene from Mycobacterium tuberculosis coding for a hypothetical 27 kDa protein and its use for the specific PCR identification of these mycobacteria. 1097 Jul 28

Microwave heating of histologic sections in citrate buffer (MAR) is a widely used method of antigen recovery but often results in loss of tissue sections. Low-temperature antigen retrieval (LTAR), incubation at 80 degrees C in citrate buffer for 2 hours with trypsin pretreatment is an alternative method reported to result in better antigen recovery for specific antigens as well as decreased loss of tissue sections. To optimize our immunohistochemical evaluation of breast carcinomas, we compared the efficacy of these methods of antigen recovery for several important antigens. Ten breast carcinomas were immunostained for estrogen and progesterone receptors (ER and PR), Ki-67/ MIB 1, p27/Kip-1, and Bcl-2 after MAR, LTAR with enzymatic pretreatment, or no antigen recovery. The immunohistochemical staining was scored and compared for each antibody and antigen recovery combination. The proportion of tissue lost from each slide after staining also was assessed. More and stronger positive staining was achieved with antibodies to Ki67/MIB 1 and ER when LTAR was used compared with the other two methods; in contrast, optimal staining with antibodies to Bcl-2 was achieved when MAR was used. Staining with anti-p27/Kip- was nearly equal with either LTAR or MAR. Staining with anti-PR was slightly better with MAR than with LTAR. Tissue loss was greatest for MAR compared with LTAR or with no antigen recovery. For selected cases, LTAR caused focal tissue damage, and either the immunostaining with LTAR had to be repeated or only a portion of some tissue sections would be used for examination. LTAR was the most effective for ER and Ki-67/MIB 1. MAR provided the most intense staining for Bcl-2 and PR, but this enhanced staining must be weighed against the greater tissue section loss from MAR. This study demonstrated that AR methods are not equally applicable to all antibodies.
Appl Immunohistochem Mol Morphol 2000 Sep
PMID:Methods of antigen recovery vary in their usefulness in unmasking specific antigens in immunohistochemistry. 1098 77

Ubiquitin-proteasome-mediated destruction of rate-limiting proteins is required for timely progression through the main cell cycle transitions. The anaphase-promoting complex (APC), periodically activated by the Cdh1 subunit, represents one of the major cellular ubiquitin ligases which, in Saccharomyces cerevisiae and Drosophila spp., triggers exit from mitosis and during G(1) prevents unscheduled DNA replication. In this study we investigated the importance of periodic oscillation of the APC-Cdh1 activity for the cell cycle progression in human cells. We show that conditional interference with the APC-Cdh1 dissociation at the G(1)/S transition resulted in an inability to accumulate a surprisingly broad range of critical mitotic regulators including cyclin B1, cyclin A, Plk1, Pds1, mitosin (CENP-F), Aim1, and Cdc20. Unexpectedly, although constitutively assembled APC-Cdh1 also delayed G(1)/S transition and lowered the rate of DNA synthesis during S phase, some of the activities essential for DNA replication became markedly amplified, mainly due to a progressive increase of E2F-dependent cyclin E transcription and a rapid turnover of the p27(Kip1) cyclin-dependent kinase inhibitor. Consequently, failure to inactivate APC-Cdh1 beyond the G(1)/S transition not only inhibited productive cell division but also supported slow but uninterrupted DNA replication, precluding S-phase exit and causing massive overreplication of the genome. Our data suggest that timely oscillation of the APC-Cdh1 ubiquitin ligase activity represents an essential step in coordinating DNA replication with cell division and that failure of mechanisms regulating association of APC with the Cdh1 activating subunit can undermine genomic stability in mammalian cells.
Mol Cell Biol 2000 Oct
PMID:Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis. 1100 57

Jagged2 is a member of the DSL (Delta-Serrate-Lag-2) -ligand family of transmembrane proteins that signal through the Notch receptors. In many cases of human acute lymphoblastic T-cell leukemias, chromosomal translocations fuse a part of the Notch-1 gene to the T-cell receptor-beta locus (Ellison et al., 1991, Cell 66:649-661). The truncated Notch-1 allele encodes an aberrant protein that lacks most of the extracellular domain and is constitutively activated (Pear et al., 1996, J Exp Med 183:2283-2291). A similarly truncated version of Notch-1 was capable of transforming primary baby rat kidney cells in cooperation with the E1A oncogene of adenovirus (Capobianco et al., 1997, Mol Cell Bio 17:6265-6273). The transformed cells grew to a high population density in culture and were tumorigenic in vivo. It was unclear what roles Notch signaling played in neoplastic transformation. In this report, we demonstrate that sustained activation of the Jagged2/Notch signal transduction pathway induced continuous cell cycling in confluent rabbit-skin fibroblasts sensitive to density-dependent inhibition of cell division. The ability to overcome density-dependent inhibition of cell division correlated with elevated cyclin-dependent kinase-2 (CDK2) activity and a lower level of induction of the CDK inhibitor p27 in the target cells. Similar cell-cycle effect was seen when a truncated mouse Notch-1 construct with constitutive activity was expressed. Taken together, our findings indicate that sustained activation of the Jagged2/Notch signal transduction pathway can overcome density-dependent inhibition of cell division and therefore may contribute to neoplastic transformation.
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PMID:Jagged2 induces cell cycling in confluent fibroblasts susceptible to density-dependent inhibition of cell division. 1105 13


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