Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we identified a client-binding site of Cdc37 that is required for its association with protein kinases. Phage display technology and liquid chromatography-tandem mass spectrometry (which identifies a total of 33 proteins) consistently identify a unique sequence, GXFG, as a Cdc37-interacting motif that occurs in the canonical glycine-rich loop (GXGXXG) of protein kinases, regardless of their dependence on Hsp90 or Cdc37. The glycine-rich motif of Raf-1 (GSGSFG) is necessary for its association with Cdc37; nevertheless, the N lobe of Raf-1 (which includes the GSGSFG motif) on its own cannot interact with Cdc37. Chimeric mutants of Cdk2 and Cdk4, which differ sharply in their affinities toward Cdc37, show that their C-terminal portions may determine this difference. In addition, a nonclient kinase, the catalytic subunit of cyclic AMP-dependent protein kinase, interacts with Cdc37 but only when a threonine residue in the activation segment of its C lobe is unphosphorylated. Thus, although a region in the C termini of protein kinases may be crucial for accomplishing and maintaining their interaction with Cdc37, we conclude that the N-terminal glycine-rich loop of protein kinases is essential for physically associating with Cdc37.
 ...
PMID:Cdc37 interacts with the glycine-rich loop of Hsp90 client kinases. 1661 82

In a series of colorectal cancer cell lines, both necrosis and apoptosis were induced upon exposure to oxaliplatin, and enhanced by co-administration of the Hsp90 inhibitor 17-AAG. We analyzed the effects of these interventions on the cell cycle, and found that oxaliplatin treatment caused G1 and G2 arrest in HCT116 cells, and S-phase accumulation in two p53-deficient cell lines (HT29 and DLD1). Addition of 17-AAG enhanced cell cycle effects of oxaliplatin in HCT116, and induced G1 arrest and decrease in S-phase population in the other cell lines. Analysis of cell cycle proteins revealed that the major difference between the cell lines was that in HCT116, 17-AAG resulted in profound inhibition of expression and phosphorylation of late G1 proteins cyclin E and cdk2, with no effect on p21/WAF1 induction. Consistent with these, an HCT116 p53(-/-) line, lacking p21, showed resistance to oxaliplatin, failure to enter apoptosis, and an accumulation of cells in S-phase. Introduction of p21 in these cells caused reversal of that phenotype, including restoration of the G1 block and re-sensitization to oxaliplatin. Inhibition of G1/S progression using cdk2 inhibitor also enhanced oxaliplatin cytotoxicity. We conclude that in colon cancer cells with impaired p53 function, interventions directed to cycle arrest in G1 may potentiate oxaliplatin activity.
 ...
PMID:Inhibition of G1/S transition potentiates oxaliplatin-induced cell death in colon cancer cell lines. 1734 30

The last decade has witnessed the introduction of a large number of novel, molecularly targeted agents into the therapeutic armamentarium against diverse forms of cancer, including leukemia. Such agents include signal transduction, cell cycle, histone deacetylase, Hsp90, proteasome, and Bcl-2 family member inhibitors, among others. While most of these agents have been or are currently being evaluated in adult patients with acute leukemia, experience in childhood leukemia is very limited. Although the use of such targeted agents as potentiators of conventional cytotoxic agent activity represents a logical approach, an emerging body of evidence suggests that neoplastic cells in general, and leukemic cells in particular, are highly susceptible to a therapeutic strategy in which survival signaling and cell cycle regulatory pathways are simultaneously disrupted. In in vitro studies, highly synergistic antileukemic interactions have been reported between CDK and HDAC inhibitors; HDAC and proteasome inhibitors; Bcl-2 antagonists and CDK inhibitors; MEK/ERK and Chk1 inhibitors, and proteasome and CDK inhibitors, among other combinations. Some of these strategies, including combinations of HDAC and CDK inhibitors, and CDK and proteasome inhibitors, have now entered the clinical arena in patients with leukemia and other hematologic malignancies. Based upon preclinical results to date, there is reason to suspect that such strategies might prove to be active against several types of childhood leukemia. Thus, over the next decade, the introduction of molecularly targeted agents, alone and in combination, into the therapeutic armamentarium against childhood leukemia may have significant implications for children with this disease.
 ...
PMID:Simultaneous interruption of signal transduction and cell cycle regulatory pathways: implications for new approaches to the treatment of childhood leukemias. 1758 30

The Hsp70-Hsp90 complex is implicated in the folding and regulation of numerous signaling proteins, and Hop, the Hsp70-Hsp90 Organizing Protein, facilitates the association of this multichaperone machinery. Phosphatase treatment of mouse cell extracts reduced the number of Hop isoforms compared to untreated extracts, providing the first direct evidence that Hop was phosphorylated in vivo. Furthermore, surface plasmon resonance (SPR) spectroscopy showed that a cdc2 kinase phosphorylation mimic of Hop had reduced affinity for Hsp90 binding. Hop was predominantly cytoplasmic, but translocated to the nucleus in response to heat shock. A putative bipartite nuclear localization signal (NLS) has been identified within the Hsp90-binding domain of Hop. Although substitution of residues within the major arm of this proposed NLS abolished Hop-Hsp90 interaction as determined by SPR, this was not sufficient to prevent the nuclear accumulation of Hop under leptomycin-B treatment and heat shock conditions. These results showed for the first time that the subcellular localization of Hop was stress regulated and that the major arm of the putative NLS was not directly important for nuclear translocation but was critical for Hop-Hsp90 association in vitro. We propose a model in which the association of Hop with Hsp90 and the phosphorylated status of Hop both play a role in the mechanism of nucleo-cytoplasmic shuttling of Hop.
 ...
PMID:Nuclear translocation of the phosphoprotein Hop (Hsp70/Hsp90 organizing protein) occurs under heat shock, and its proposed nuclear localization signal is involved in Hsp90 binding. 1828 Feb 55

Cyclin E is the Cdk2-regulatory subunit required for the initiation of DNA replication at the G1/S transition. It accumulates in late G1 phase and gets rapidly degraded by the ubiquitin/proteasome pathway during S phase. The degradation of cyclin E is a consequence of its phosphorylation and subsequent isomerization by the peptidyl-prolyl isomerase Pin1. We show that in the colon cancer cells HT-29 the inhibition of the chaperone function of Hsp90 by geldanamycin (GA) enhances the ubiquitinylation of cyclin E and triggers active degradation via the proteasome pathway. As Hsp90 forms multiprotein complexes with and regulates the function and cell contents of numerous signaling proteins, this observation suggests a direct interaction between Hsp90 and cyclin E. However, experiments using cell lysate fractionation did not reveal the presence of complexes containing both Hsp90 and cyclin E. Coupled transcription/translation experiments also failed to detect the formation of complexes between newly synthesized cyclin E and Hsp90. We conclude that Hsp90 can regulate the degradation of cellular proteins without binding to them, by an indirect mechanism. This conclusion postulates a new category of proteins that are affected by the inactivation of Hsp90. Our observations do not support the possible involvement of a PPIase in this indirect mechanism. Besides, we did not observe active geldanamycin-dependent degradation of cyclin E in the prostate cancer-derived cell line DU-145, indicating that the Hsp90-dependent stabilization of cyclin E requires specific regulatory mechanism which may be lost in certain types of cancer cells.
 ...
PMID:Indirect participation of Hsp90 in the regulation of the cyclin E turnover. 1897 5

Cancer cells frequently exhibit overduplicated centrosomes that lead to formation of multipolar spindles, chromosome missegregation, and aneuploidy. However, the molecular events involved in centrosome overduplication remain largely unknown. Experimentally, centrosome overduplication is observed in p53-deficient cells arrested in S phase with hydroxyurea. Using this assay, we have identified distinct roles for Cdk2, microtubules, dynein, and Hsp90 in the overduplication of functional centrosomes in mammalian cells and show that Cdk2 is also required for the generation of centriolar satellites. Moreover, we demonstrate that nuclear export is required for centriolar satellite formation and centrosome overduplication, with export inhibitors causing a Cdk-dependent accumulation of nuclear centrin granules. Hence, we propose that centrosome precursors may arise in the nucleus, providing a novel mechanistic explanation for how nuclear Cdk2 can promote centrosome overduplication in the cytoplasm. Furthermore, this study defines a molecular pathway that may be targeted to prevent centrosome overduplication in S-phase-arrested cancer cells.
 ...
PMID:Molecular dissection of the centrosome overduplication pathway in S-phase-arrested cells. 1913 75

Temperature affects diverse biological processes. In fungi such as the pathogen Candida albicans, temperature governs a morphogenetic switch between yeast and hyphal growth. A new report connects the thermosensor Hsp90 to a CDK-cyclin-transcription factor module that controls morphogenesis.
 ...
PMID:Fungal morphogenesis: in hot pursuit. 2236 51

In Schizosaccharomyces pombe, cytokinesis occurs by ordered recruitment of actomyosin components at the division site, followed by lateral condensation to produce a ring-like structure early in anaphase, which eventually matures and contracts at the end of mitosis. We found that in temperature-sensitive hsp90-w1 mutant cells, encoding an Hsp90 mutant protein, ring components were recruited to form a cortical network at the division site, but this network failed to condense into a compact ring, suggesting a role for Hsp90 in this particular step. hsp90-w1 mutant shows strong genetic interaction with specific mutant alleles of the fission yeast cdc2, such as cdc2-33. Interestingly, actomyosin ring defects in hsp90-w1 cdc2-33 mutant cells resembled that of hsp90-w1 single mutant at restrictive temperature. Noteworthy, similar genetic interaction was found with a mutant allele of polo-like kinase, plo1-ts4, suggesting that Hsp90 collaborates with Cdc2 and Plo1 cell cycle kinases to condense medial ring components. In vitro analyses suggested that Cdc2 and Plo1 physically interact with Hsp90. Association of Cdc2 to Hsp90 was ATP independent, while Plo1 binds to this chaperone in an ATP-dependent manner, indicating that these two kinases interact with different Hsp90 complexes. Overall, our analyses of hsp90-w1 reveal a possible role for this chaperone in medial ring condensation in association with Cdc2 and Plo1 kinases.
 ...
PMID:Hsp90 interaction with Cdc2 and Plo1 kinases contributes to actomyosin ring condensation in fission yeast. 2254 82

Peptidyl prolyl isomerases (PPIases) are proteins belonging to the immunophilin family and are characterised by their cis-trans isomerization activity at the X-Pro peptide bond, in addition to their tetratricopeptide repeat (TPR) domain, important for interaction with the molecular chaperone, Hsp90. Due to this unique structure these proteins are able to facilitate protein-protein interactions which can impact significantly on a range of cellular processes such as cell signalling, differentiation, cell cycle progression, metabolic activity and apoptosis. Malfunction and/or dysregulation of most members of this class of proteins promotes cellular damage and tissue/organ failure, predisposing to ageing and age-related diseases. Many individual genes within the PPIase family are associated with several age-related diseases including cardiovascular diseases (CVDs), atherosclerosis, type II diabetes mellitus (T2D), chronic kidney disease (CDK), neurodegeneration, cancer and age-related macular degeneration (AMD), in addition to the ageing process itself. This review will focus on the different roles of PPIases, and their therapeutic/ biomarker potential in these age-related vascular diseases.
...
PMID:The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases. 2598 61

6BrCaQ is a promising anti-cancer agent derived from novobiocin, which has been shown to inhibit Hsp90. 6BrCaQ was loaded into nanometer-scaled phospholipid vesicles (liposomes) suitable for drug delivery to solid tumors. The effective incorporation of the drug within the phospholipid bilayer was investigated by differential scanning calorimetry. Liposomal 6BrCaQ showed good activity on PC-3 cell lines in vitro in terms of apoptosis induction and cell growth arrest in G2/M. Liposomes containing 6BrCaQ were also shown to slow down migration of PC-3 cells in presence of chemokine ligand 2 and to synergize with doxorubicin. Several Hsp90 targeting molecules like geldanamycin induce accumulation of Hsp70, leading to cytoprotection and often correlated with poor prognosis. In this study, we did not report any Hsp70 induction after treatment with liposomal 6BrCaQ but a decrease in Hsp90 and CDK-4 protein expression, indicating an effect on the chaperon machinery. Liposomal encapsulation of 6BrCaQ revealed promising anti-cancer effects and a better understanding of its mechanism of action.
...
PMID:Formulation and in vitro efficacy of liposomes containing the Hsp90 inhibitor 6BrCaQ in prostate cancer cells. 2672 24


<< Previous 1 2 3 4 Next >>