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41.
Progression through the early G(1) phase of the cell cycle requires mitogenic stimulation, which ultimately leads to the activation of cyclin-dependent kinases 4 and 6 (Cdk4/6). Cdk4/6 activity is promoted by D-type cyclins and opposed by Cdk inhibitor proteins. Loss of c-myc proto-oncogene function results in a defect in the activation of Cdk4/6. c-myc(-/-) cells express elevated levels of the Cdk inhibitor p27(Kip1) and reduced levels of Cdk7, the catalytic subunit of Cdk-activating kinase. We show here that in normal (c-myc(+/+)) cells, the majority of cyclin D-Cdk4/6 complexes are assembled with p27 and remain inactive during cell cycle progression; their function is presumably to sequester p27 from Cdk2 complexes. A small fraction of Cdk4/6 protein was found in lower molecular mass catalytically active complexes. Conditional overexpression of p27 in c-myc(+/+) cells caused inhibition of Cdk4/6 activity and elicited defects in G(0)-to-S phase progression very similar to those seen in c-myc(-/-) cells. Overexpression of cyclin D1 in c-myc(-/-) cells rescued the defect in Cdk4/6 activity, indicating that the limiting factor is the number of cyclin D-Cdk4/6 complexes. Cdk-activating kinase did not rescue Cdk4/6 activity. We propose that the defect in Cdk4/6 activity in c-myc(-/-) cells is caused by the elevated levels of p27, which convert the low abundance activable cyclin D-Cdk4/6 complexes into unactivable complexes containing higher stoichiometries of p27. These observations establish p27 as a physiologically relevant regulator of cyclin D-Cdk4/6 activity as well as mechanistically a target of c-Myc action and provide a model by which c-Myc influences the early-to-mid G(1) phase transition. 相似文献
42.
Usacheva A Sandoval R Domanski P Kotenko SV Nelms K Goldsmith MA Colamonici OR 《The Journal of biological chemistry》2002,277(50):48220-48226
Kinases of the Jak family (Jak1/2/3 and Tyk2) interact with the membrane proximal domain of different cytokine receptors and play a critical role in the activation of cytokine and growth factor signaling pathways. In this report we demonstrate that both the Box 1 and Box 2 motif collaborate in the association and activation of Jak1 by type I interferons. Mutational analysis of the beta chain of type I interferon receptor (IFNalphaRbetaL/IFNAR2) revealed that Box 1 plays a more significant role in activation than in the association with Jak1. On the contrary, the Box 2 motif contributes more to the association with Jak1 than to kinase activation. Additionally, the study of the Jak1 binding sites on the IL2 receptor beta (IL2Rbeta), IFNgammaRalpha/IFNGR1, and IL10Ralpha/IL10R1 chains suggests that cytokine receptors have two different kinds of interaction with Jak1. One form of interaction involves the Box 1 and the previously described Box 2 motif, which we now designate as Box 2A, characterized by the VEVI and LEVL sequences present in IFNalphaRbetaL/IFNAR2 and IL2Rbeta subunits, respectively. The second form of interaction requires a motif termed Box 2B, which is present in the IFNgammaRalpha/IFNGR1 (SILLPKS) and IL10Ralpha/IL10R1 (SVLLFKK) chains. Interestingly, Box 2B localizes close to the membrane region (8-10 amino acids from the membrane) similar to Box 1, whereas Box 2A is more distal (38-58 amino acids from the membrane). 相似文献
43.
Krause CD Lunn CA Izotova LS Mirochnitchenko O Kotenko SV Lundell DJ Narula SK Pestka S 《The Journal of biological chemistry》2000,275(30):22995-23004
Interferon-gamma (IFN-gamma) and its receptor complex are dimeric and bilaterally symmetric. We created mutants of IFN-gamma that bind only one IFN-gammaR1 chain per dimer molecule (called a monovalent IFN-gamma) to see if the interaction of IFN-gamma with one-half of the receptor complex is sufficient for bioactivity. Mutating a receptor-binding sequence in either AB loop of a covalent dimer of IFN-gamma yielded two monovalent IFN-gammas, gamma(m)-gamma and gamma-gamma(m), which cross-link to only a single soluble IFN-gammaR1 molecule in solution and on the cell surface. Monovalent IFN-gamma competes fully with wild type IFN-gamma for binding to U937 cells but only at a greater than 100-fold higher concentration than wild type IFN-gamma. Monovalent IFN-gamma had anti-vesicular stomatitis virus activity and antiproliferative activity, and it induced major histocompatibility complex class I and class II (HLA-DR) expression. In contrast, the maximal levels of activated Stat1alpha produced by monovalent IFN-gammas after 15 min were never more than half of those produced by either wild type or covalent IFN-gammas in human cell lines. These data indicate that while monovalent IFN-gamma activates only one-half of a four-chain receptor complex, this is sufficient for Stat1alpha activation, major histocompatibility complex class I surface antigen induction, and antiviral and antiproliferative activities. Thus, while interaction with both halves of the receptor complex is required for high affinity binding of IFN-gamma and efficient signal transduction, interaction with only one-half of the receptor complex is sufficient to initiate signal transduction. 相似文献
44.
The objective of this work was to prepare and evaluate ketorolac tromethamine-loaded albumin microspheres using a factorial
design. Albumin microspheres were prepared by emulsion cross-linking method. Selected formulations were characterized for
their entrapment efficiency, particle size, surface morphology, and release behavior. Analysis of variance (ANOVA) for entrapment
efficiency indicated that entrapment efficiency is best fitted to a response surface linear model. From the statistical analysis
it was observed that as the drug:polymer (D∶P) ratio and volume of glutaraldehyde increased, there was a significant increase
in the encapsulation efficiency. Scanning electron microscopy of the microspheres revealed a spherical, nonporous and uniform
appearance, with a smooth surface. Based on the entrapment efficiency and physical appearance, 9 formulations were selected
for release study. The maximum particle size observed was below 40 μm. The release pattern was biphasic, characterized by
an initial burst effect followed by a slow release. All selected microspheres, except those having less polymer proportion
(D∶P ratio is 1∶1), exhibited a prolonged release for almost 24 hours. On comparingr
2 values for Higuchi and Peppas kinetic models, different batches of microspheres showed Fickian, non-Fickian, and diffusion
kinetics. The release mechanism was regulated by D∶P ratio and amount of cross-linking agent. From the experimental data obtained
with respect to particle size and extent of drug relaase, it could be concluded that the prepared microspheres are useful
for once-a-day intramuscular administration of ketorolac tromethamine.
Published: February 23, 2007 相似文献
45.
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47.
The human brain library carried in the EMBL3 vector was employed for isolating prointerleukin 1 beta genomic sequences using three synthetic 20-member oligonucleotides. Oligonucleotides were homologous to the following mRNA regions: 3'-nontranslated region/C1/, 3'-translated region of mRNA/C2/ and the sequence coding N-terminal of mature protein/N1/. The oligonucleotide labeling utilized the terminal nucleotidyltransferase and [alpha-32P] dATP and specific activity of labeled oligonucleotides reached 1.6.10(10) cpm. The sizes of the synthesized labeled sequences (tails) were about 10 b.p. Hybridization probe C1 was used for the first screening and 24 hybridization positive clones were detected. For the next screening probe C2 was used and only 2 hybridization positive clones with different level of hybridization were detected from 24 clones. Probe N1 was used for the third screening and allowed to identify the only positive clone. The characterization by restriction mapping and Southern blot analyses have shown that recombinant phage DNA contains all three exons, coding the mature interleukin 1 beta. Some fragments were recloned to tg130 vector phage and nucleotide sequences of exon 5 (completely) and exon 7, intron 4 and 5 (partially) were determined. 相似文献
48.
B P Pollack S V Kotenko W He L S Izotova B L Barnoski S Pestka 《The Journal of biological chemistry》1999,274(44):31531-31542
To expand our understanding of the role of Jak2 in cellular signaling, we used the yeast two-hybrid system to identify Jak2-interacting proteins. One of the clones identified represents a human homologue of the Schizosaccaromyces pombe Shk1 kinase-binding protein 1, Skb1, and the protein encoded by the Saccharomyces cerevisiae HSL7 (histone synthetic lethal 7) gene. Since no functional motifs or biochemical activities for this protein or its homologues had been reported, we sought to determine a biochemical function for this human protein. We demonstrate that this protein is a protein methyltransferase. This protein, designated JBP1 (Jak-binding protein 1), and its homologues contain motifs conserved among protein methyltransferases. JBP1 can be cross-linked to radiolabeled S-adenosylmethionine (AdoMet) and methylates histones (H2A and H4) and myelin basic protein. Mutants containing substitutions within a conserved region likely to be involved in AdoMet binding exhibit little or no activity. We mapped the JBP1 gene to chromosome 14q11.2-21. In addition, JBP1 co-immunoprecipitates with several other proteins, which serve as methyl group acceptors and which may represent physiological targets of this methyltransferase. Messenger RNA for JBP1 is widely expressed in human tissues. We have also identified and sequenced a homologue of JBP1 in Drosophila melanogaster. This report provides a clue to the biochemical function for this conserved protein and suggests that protein methyltransferases may have a role in cellular signaling. 相似文献
49.
Walid Abushahba Murugabaskar Balan Ismael Castaneda Yao Yuan Kenneth Reuhl Elizabeth Raveche Andrew de la Torre Ahmed Lasfar Sergei V. Kotenko 《Cancer immunology, immunotherapy : CII》2010,59(7):1059-1071
Hepatocellular carcinoma (HCC) occurs most commonly secondary to cirrhosis due to chronic hepatitis C or B virus (HCV/HBV)
infections. Type I interferon (IFN-α) treatment of chronic HCV/HBV infections reduces the incidence of HCC in cirrhotic patients.
However, IFN-α toxicity limits its tolerability and efficacy highlighting a need for better therapeutic treatments. A recently
discovered type III IFN (IFN-λ) has been shown to possess antiviral properties against HCV and HBV in vitro. In phase I clinical
trials, IFN-λ treatment did not cause significant adverse reactions. Using a gene therapy approach, we compared the antitumor
properties of IFN-α and IFN-λ in a transplantable hepatoma model of HCC. BALB/c mice were inoculated with syngeneic BNL hepatoma
cells, or BNL cells expressing IFN-λ (BNL.IFN-λ cells) or IFN-α (BNL.IFN-α cells). Despite the lack of antiproliferative activity
of IFNs on BNL cells, both BNL.IFN-λ and BNL.IFN-α cells displayed retarded growth kinetics in vivo. Depletion of NK cells
from splenocytes inhibited splenocyte-mediated cytotoxicity, demonstrating that NK cells play a role in IFN-induced antitumor
responses. However, isolated NK cells did not respond directly to IFN-λ. There was also a marked NK cell infiltration in IFN-λ
producing tumors. In addition, IFN-λ and, to a lesser extent, IFN-α enhanced immunocytotoxicity of splenocytes primed with
irradiated BNL cells. Splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN-γ, and mediated by dendritic
cells. In contrast to NK cells, isolated from spleen CD11c+ and mPDCA+ dendritic cells responded directly to IFN-λ. The antitumor
activities of IFN-λ against hepatoma, in combination with HCV and HBV antiviral activities warrant further investigation into
the clinical use of IFN-λ to prevent HCC in HCV/HBV-infected cirrhotic patients, as well as to treat liver cancer. 相似文献
50.
Analysis of optimal phenotypic space using elementary modes as applied to Corynebacterium glutamicum