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Query: UNIPROT:P06889 (Mol)
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The role of small heat shock proteins (sHsps) as molecular chaperones is still poorly understood. We therefore investigated the effect of proteasomal inhibition on sHsps in the rat cardiac myoblast cell line H9c2. Proteasomes are responsible for controlled degradation of intracellular proteins. Inhibition of their activities leads to accumulation of unfolded proteins, which can form insoluble "aggresomes" together with proteasomes and heat shock proteins Hsp70 and Hsp90. We here report that upon proteasome inhibition, alpha B-crystallin and Hsp25 translocate from the detergent-soluble cytosolic fraction to the detergent-insoluble nuclear/cytoskeletal fraction. Although phosphorylation of both alpha B-crystallin and Hsp25 is induced, this does not seem to be essential for the translocation. Immunocytochemistry revealed that alpha B-crystallin and Hsp25, which show a diffuse cytoplasmic staining in unstressed H9c2 cells, colocalize with F-actin upon proteasomal inhibition. After transfection in H9c2 cells, other sHsps (alpha A-crystallin, Hsp20, HspB2 and HspB3) showed similar translocation to the actin cytoskeleton. The redistribution of sHsps upon proteasomal inhibition may reflect a mechanism by which cells are protected from damaged intracellular proteins by sequestering them on the cytoskeleton.
J Mol Cell Cardiol 2002 Feb
PMID:Translocation of small heat shock proteins to the actin cytoskeleton upon proteasomal inhibition. 1185 48

The IKK complex, containing two catalytic subunits IKKalpha and IKKbeta and a regulatory subunit NEMO, plays central roles in signal-dependent activation of NF-kappaB. We identify Cdc37 and Hsp90 as two additional components of the IKK complex. IKKalpha/IKKbeta/NEMO and Cdc37/Hsp90 form an approximately 900 kDa heterocomplex, which is assembled via direct interactions of Cdc37 with Hsp90 and with the kinase domain of IKKalpha/IKKbeta. Geldanamycin (GA), an antitumor agent that disrupts the formation of this heterocomplex, prevents TNF-induced activation of IKK and NF-kappaB. GA treatment reduces the size of the IKK complex and abolishes TNF-dependent recruitment of the IKK complex to TNF receptor 1 (TNF-R1). Therefore, heterocomplex formation with Cdc37/Hsp90 is a prerequisite for TNF-induced activation and trafficking of IKK from the cytoplasm to the membrane.
Mol Cell 2002 Feb
PMID:TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. 1186 12

The estrogen receptor (ER) is a hormone-dependent transcription factor that belongs to the steroid/thyroid hormone receptor superfamily. Since the ER contributes to development and progression in human breast cancer, a number of studies have explored ways to inactivate this receptor. Previous studies have suggested that the 90-kDa heat shock protein (Hsp90) interacts with the ER, thus stabilizing the receptor in an inactive state. Here, we report that radicicol, an Hsp90-specific inhibitor, repressed estrogen-dependent transactivation of the ER as measured by pS2 gene transcription and a reporter gene encoding an estrogen-responsive element. Furthermore, we showed that radicicol induced rapid degradation of ERalpha, while the amount of ubiquitinated ERalpha was increased. A proteasome inhibitor, LLnL, almost completely abrogated the radicicol-induced decrease in expression level, as well as in transcriptional activity of ERalpha. These results suggest that radicicol disrupts the ER-Hsp90 heterodimeric complex, thereby generating ERalpha that is susceptible to ubiquitin/proteasome-induced degradation.
Mol Cell Endocrinol 2002 Feb 25
PMID:Radicicol represses the transcriptional function of the estrogen receptor by suppressing the stabilization of the receptor by heat shock protein 90. 1191 45

The Cdc37 protein in Saccharomyces cerevisiae is thought to be a kinase-targeting subunit of the chaperone Hsp90. In a genetic screen, four protein kinases were identified as interacting with Cdc37 - Cdc5, Cdc7, Cdc15 and Cak1. This result underlines the importance of Cdc37 for the folding of protein kinases. In addition, we showed that Ydj1, a yeast DnaJ homolog belonging to the Hsp40 family of chaperones, genetically interacts with Cdc37. No physical interaction has so far been detected between Cdc37 and Cdc28, although genetic interactions (synthetic lethality and mutation suppression), and biochemical studies have suggested that these two proteins functionally interact. We found that, when separately expressed, the N-terminal lobe of Cdc28 interacted strongly with the C-terminal moiety of Cdc37 in a two-hybrid system. This was not the case for the full-length Cdc28 protein. We present models to explain these results.
Mol Genet Genomics 2002 Jun
PMID:Physical interaction of Cdc28 with Cdc37 in Saccharomyces cerevisiae. 1211 52

The Saccharomyces cerevisiae heat-shock protein (Hsp)40, Ydj1p, is involved in a variety of cellular activities that control polypeptide fate, such as folding and translocation across intracellular membranes. To elucidate the mechanism of Ydj1p action, and to identify functional partners, we screened for multicopy suppressors of the temperature-sensitive ydj1-151 mutant and identified a yeast Hsp110, SSE1. Overexpression of Sse1p also suppressed the folding defect of v-Src kinase in the ydj1-151 mutant and partially reversed the alpha-factor translocation defect. SSE1-dependent suppression of ydj1-151 thermosensitivity required the wild-type ATP-binding domain of Sse1p. However, the Sse1p mutants maintained heat-denatured firefly luciferase in a folding-competent state in vitro and restored human androgen receptor folding in sse1 mutant cells. Because the folding of both v-Src kinase and human androgen receptor in yeast requires the Hsp90 complex, these data suggest that Ydj1p and Sse1p are interacting cochaperones in the Hsp90 complex and facilitate Hsp90-dependent activity.
Mol Biol Cell 2002 Aug
PMID:Overexpression of yeast Hsp110 homolog Sse1p suppresses ydj1-151 thermosensitivity and restores Hsp90-dependent activity. 1218 44

In the fission yeast Schizosaccharomyces pombe, the wos2 gene encodes p23, a highly conserved protein which functions as a co-chaperone for the heat shock protein Hsp90. This p23 protein binds to Hsp90, but its activities and regulatory mechanisms are still unclear. Northern analysis has shown that the wos2 gene produces three transcripts of about 1.1, 0.9 and 0.8 kb, which are expressed differentially depending on the growth temperature. The largest and the smallest transcripts were most abundant at 25 degrees C, whereas the 0.9-kb transcript predominated at 37 degrees C. A time-course analysis indicated that this 0.9-kb species rapidly increased in abundance after a shift from 25 degrees C to 37 degrees C, reaching a maximum after 15 min. A shift back to 25 degrees C resulted in a decline in the amount of this transcript, albeit at a slower rate. Expression analysis of wos2:ura4 and nmt1:wos2 constructs showed that the 3' untranslated region of wos2 alone directs the formation of these multiple, discrete wos2 mRNAs. Sequence analysis of cDNAs derived from these mRNAs showed that the use of different polyadenylation sites results in the production of the three differently sized wos2 transcripts. In the case of the 0.9- and 0.8-kb mRNA species, these sites lie in a predicted hairpin loop in the mRNA, suggesting that polyadenylation signals in wos2 transcripts may be mediated by RNA secondary structure. The possibility that differential thermal stability of these hairpin structures could influence polyadenylation site choice during formation of the 3'-ends of the mRNAs is discussed.
Mol Genet Genomics 2002 Aug
PMID:Poly(A) site choice during mRNA 3'-end formation in the Schizosaccharomyces pombe wos2 gene. 1220 26

Treatment (>/=6 h) of cultured bovine adrenal chromaffin cells with geldanamycin (GA) or herbimycin A (HA), an inhibitor of the 90-kDa heat-shock protein (Hsp90) family, decreased cell surface (125)I-insulin binding. The effect of GA was concentration (EC(50) = 84 nM)- and time (t(1/2) = 8.5 h)-dependent; GA (1 microM for 24 h) lowered the B(max) value of (125)I-insulin binding by 80%, without changing the K(d) value. Western blot analysis showed that GA (>/=3 h) lowered insulin receptor (IR) level by 83% (t(1/2) = 7.4 h; EC(50) = 74 nM), while raising IR precursor level by 100% (t(1/2) = 7.9 h; EC(50) = 300 nM). Pulse-label followed by reducing and nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that monomeric IR precursor (~190 kDa) developed into the homodimeric IR precursor (approximately 380 kDa) and the mature alpha(2)beta(2) IR (~410 kDa) in nontreated cells, but not in GA-treated cells; in GA-treated cells, the homodimerization-incompetent form of monomeric IR precursor was degraded via endoplasmic reticulum (ER)-associated protein degradation. Immunoprecipitation followed by immunoblot analysis showed that IR precursor was associated with calnexin (CNX) to a greater extent in GA-treated cells, compared with nontreated cells. GA had no effect on IR mRNA levels and internalization rate of cell surface IRs. In GA-treated cells, insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated by 77%, with no change in IRS-1 level. Thus, inhibition of the Hsp90 family by GA or HA interrupts homodimerization of monomeric IR precursor in the ER and increases retention of monomeric IR precursor with CNX; this event retards cell surface expression of IR and attenuates insulin-induced activation of IRS-1.
Mol Pharmacol 2002 Oct
PMID:Down-regulation of cell surface insulin receptor and insulin receptor substrate-1 phosphorylation by inhibitor of 90-kDa heat-shock protein family: endoplasmic reticulum retention of monomeric insulin receptor precursor with calnexin in adrenal chromaffin cells. 1223 31

Aquatic ectotherms can adapt to a wide range of temperature changes, but the molecular mechanisms that underlie this adaptability are not well understood. We identified genes that are differentially expressed in the catfish ( Ictalurus punctatus) brain using a cDNA microarray approach to gain an initial understanding of adaptation to low temperature. Among 660 genes analyzed, 61 were differentially expressed when compared at 12 degrees C and 24 degrees C. Gene induction was rapid, occurring within 2 h of the temperature shift. The major categories of differentially expressed genes included (1) genes for chaperones such as Hsp70 and Hsp70/Hsp90 organizing protein; (2) genes for transcription factors and gene products involved in signal transduction pathways such as zinc-finger proteins, calmodulin kinase inhibitor, the nuclear autoantigen SG2NA, interferon regulatory factor 3, and inorganic pyrophosphatase; (3) genes involved in lipid metabolism such as TB2 and acyl CoA binding protein; and (4) genes involved in the translational machinery such as ribosomal proteins. Some genes were induced transiently, whereas others were induced in an enduring fashion. Several genes, primarily ribosomal protein genes, were down regulated, indicating reduced metabolic activities after extended incubation at the low temperature. Thus channel catfish respond to low temperature by adjusting expression of a large number of genes. The rapid induction of proteins involved in signal transductions and chaperones suggests that both de novo synthesis of cold-induced proteins and modification of existing proteins are required for adaptation and tolerance of catfish to low environmental temperature.
Mol Genet Genomics 2002 Sep
PMID:Differential gene expression in the brain of channel catfish ( Ictalurus punctatus) in response to cold acclimation. 1224 3

Under low oxygen tension, cells increase the transcription of specific genes involved in angiogenesis, erythropoiesis, and glycolysis. Hypoxia-induced gene expression depends primarily on stabilization of the alpha subunit of hypoxia-inducible factor-1 (HIF-1alpha), which acts as a heterodimeric trans-activator with the nuclear protein known as the aryl hydrocarbon receptor nuclear translocator (Arnt). The resulting heterodimer (HIF-1alpha/Arnt) interacts specifically with the hypoxia-responsive element (HRE), thereby increasing transcription of the genes under HRE control. Our results indicate that the 90-kDa heat-shock protein (Hsp90) inhibitor radicicol reduces the hypoxia-induced expression of both endogenous vascular endothelial growth factor (VEGF) and HRE-driven reporter plasmids. Radicicol treatment (0.5 microg/ml) does not significantly change the stability of the HIF-1alpha protein and does not inhibit the nuclear localization of HIF-1alpha. However, this dose of radicicol significantly reduces HRE binding by the HIF-1alpha/Arnt heterodimer. Our results, the first to show that radicicol specifically inhibits the interaction between the HIF-1alpha/Arnt heterodimer and HRE, suggest that Hsp90 modulates the conformation of the HIF-1alpha/Arnt heterodimer, making it suitable for interaction with HRE. Furthermore, we demonstrate that radicicol reduces hypoxia-induced VEGF expression to decrease hypoxia-induced angiogenesis.
Mol Pharmacol 2002 Nov
PMID:Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1alpha/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol. 1239 Dec 59

Despite extensive phylogenetic analysis of small subunit ribosomal RNA (SSUrRNA) genes, the deep-level relationships among kinetoplastids remain poorly understood, limiting our grasp of their evolutionary history, especially the origins of their bizarre mitochondrial genome organizations. In this study we examine the SSUrRNA data in the light of a new marker--cytoplasmic heat shock protein 90 (hsp90) sequences. Our phylogenetic analyses divide kinetoplastids into four main clades. Clades 1-3 include the various bodonid kinetoplastids. Trypanosomatids comprise the fourth clade. SSUrRNA analyses give vastly different and poorly supported positions for the root of the kinetoplastid tree, depending on the out-group and analysis method. This is probably due to the extraordinary length of the branch between kinetoplastids and any out-group. In contrast, almost all hsp90 analyses place the root between clade 1 (including Dimastigella, Rhynchomonas, several Bodo spp., and probably Rhynchobodo) and all other kinetoplastids. Maximum likelihood and maximum likelihood distance analyses of hsp90 protein and second codon-position nucleotides place trypanosomatids adjacent to Bodo saltans and Bodo cf. uncinatus (clade 3), as (weakly) do SSUrRNA analyses. Hsp90 first codon- plus second codon-position nucleotide analyses return a slightly different topology. We show that this may be an artifact caused, in part, by the different evolutionary behavior of first- and second-codon positions. This study provides the most robust evidence to date that trypanosomatids are descended from within bodonids and that B. saltans is a close relative of trypanosomatids. A total reevaluation of the high-level systematics within kinetoplastids is needed. We confirm that the interlocking network organization of kinetoplast DNA seen in trypanosomatids is a derived condition within kinetoplastids but suggest that open-conformation minicircles may have arisen early in kinetoplastid evolution. Further understanding of the evolution of kinetoplast structure and RNA editing is hampered by a paucity of data from basal (i.e., clade 1) bodonids.
Mol Biol Evol 2002 Dec
PMID:The evolutionary history of kinetoplastids and their kinetoplasts. 1244 99


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