Gene expression regulation by heat-shock proteins: the cardinal roles of HSF1 and Hsp90

2017 ◽  
Vol 46 (1) ◽  
pp. 51-65 ◽  
Author(s):  
Gisela I. Mazaira ◽  
Cristina Daneri-Becerra ◽  
Nadia R. Zgajnar ◽  
Cecilia M. Lotufo ◽  
Mario D. Galigniana
Keyword(s):  
Gene Expression ◽  
Heat Shock ◽  
Protein Function ◽  
Histone Deacetylases ◽  
Tertiary Structure ◽  
Gene Expression Regulation ◽  
Heat Shock Protein 90 ◽  
Heat Shock Factor 1 ◽  
Client Proteins ◽  
Shock Proteins

The ability to permit gene expression is managed by a set of relatively well known regulatory mechanisms. Nonetheless, this property can also be acquired during a life span as a consequence of environmental stimuli. Interestingly, some acquired information can be passed to the next generation of individuals without modifying gene information, but instead by the manner in which cells read and process such information. Molecular chaperones are classically related to the proper preservation of protein folding and anti-aggregation properties, but one of them, heat-shock protein 90 (Hsp90), is a refined sensor of protein function facilitating the biological activity of properly folded client proteins that already have a preserved tertiary structure. Interestingly, Hsp90 can also function as a critical switch able to regulate biological responses due to its association with key client proteins such as histone deacetylases or DNA methylases. Thus, a growing amount of evidence has connected the action of Hsp90 to post-translational modifications of soluble nuclear factors, DNA, and histones, which epigenetically affect gene expression upon the onset of an unfriendly environment. This response is commanded by the activation of the transcription factor heat-shock factor 1 (HSF1). Even though numerous stresses of diverse nature are known to trigger the stress response by activation of HSF1, it is still unknown whether there are different types of molecular sensors for each type of stimulus. In the present review, we will discuss various aspects of the regulatory action of HSF1 and Hsp90 on transcriptional regulation, and how this regulation may affect genetic assimilation mechanisms and the health of individuals.

scholarly journals Mechanisms of Hsp90 regulation

2016 ◽  
Vol 473 (16) ◽  
pp. 2439-2452 ◽  
Author(s):  
Chrisostomos Prodromou
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein 90 ◽  
Regulatory Mechanisms ◽  
Heat Shock Factor 1 ◽  
Post Translational Modification ◽  
Regulatory Processes ◽  
Hsp90 Activity ◽  
Important Regulator ◽  
Client Proteins ◽  
The Many

Heat shock protein 90 (Hsp90) is a molecular chaperone that is involved in the activation of disparate client proteins. This implicates Hsp90 in diverse biological processes that require a variety of co-ordinated regulatory mechanisms to control its activity. Perhaps the most important regulator is heat shock factor 1 (HSF1), which is primarily responsible for upregulating Hsp90 by binding heat shock elements (HSEs) within Hsp90 promoters. HSF1 is itself subject to a variety of regulatory processes and can directly respond to stress. HSF1 also interacts with a variety of transcriptional factors that help integrate biological signals, which in turn regulate Hsp90 appropriately. Because of the diverse clientele of Hsp90 a whole variety of co-chaperones also regulate its activity and some are directly responsible for delivery of client protein. Consequently, co-chaperones themselves, like Hsp90, are also subject to regulatory mechanisms such as post translational modification. This review, looks at the many different levels by which Hsp90 activity is ultimately regulated.

scholarly journals Multifaceted roles of HEAT SHOCK PROTEIN 90 molecular chaperones in plant development

2020 ◽  
Vol 71 (14) ◽  
pp. 3966-3985 ◽  
Author(s):  
Tereza Tichá ◽  
Despina Samakovli ◽  
Anna Kuchařová ◽  
Tereza Vavrdová ◽  
Jozef Šamaj
Keyword(s):  
Heat Shock ◽  
Plant Development ◽  
Molecular Chaperones ◽  
Current Knowledge ◽  
Heat Shock Protein 90 ◽  
Molecular Networks ◽  
Genetic Perturbations ◽  
Client Proteins ◽  
Developmental Signalling ◽  
Shock Proteins

Abstract HEAT SHOCK PROTEINS 90 (HSP90s) are molecular chaperones that mediate correct folding and stability of many client proteins. These chaperones act as master molecular hubs involved in multiple aspects of cellular and developmental signalling in diverse organisms. Moreover, environmental and genetic perturbations affect both HSP90s and their clients, leading to alterations of molecular networks determining respectively plant phenotypes and genotypes and contributing to a broad phenotypic plasticity. Although HSP90 interaction networks affecting the genetic basis of phenotypic variation and diversity have been thoroughly studied in animals, such studies are just starting to emerge in plants. Here, we summarize current knowledge and discuss HSP90 network functions in plant development and cellular homeostasis.

scholarly journals Heat Shock Protein 90 in Alzheimer’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Jiang-Rong Ou ◽  
Meng-Shan Tan ◽  
An-Mu Xie ◽  
Jin-Tai Yu ◽  
Lan Tan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Protein Misfolding ◽  
Senile Plaques ◽  
Heat Shock Protein 90 ◽  
Heat Shock Factor 1 ◽  
Shock Proteins ◽  
Protein Misfolding And Aggregation

Alzheimer’s disease (AD) is the first most common neurodegenerative disease. Despite a large amount of research, the pathogenetic mechanism of AD has not yet been clarified. The two hallmarks of the pathology of AD are the extracellular senile plaques (SPs) of aggregated amyloid-beta (Aβ) peptide and the accumulation of the intracellular microtubule-associated protein tau into fibrillar aggregates. Heat shock proteins (HSPs) play a key role in preventing protein misfolding and aggregation, and Hsp90 can be viewed as a ubiquitous molecular chaperone potentially involved in AD pathogenesis. A role of Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1), the master regulator of the heat shock response. In AD, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70. Therefore, we review here to further discuss the recent advances and challenges in targeting Hsp90 for AD therapy.

scholarly journals Phase I Pharmacokinetic and Pharmacodynamic Study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an Inhibitor of Heat-Shock Protein 90, in Patients With Advanced Solid Tumors

2010 ◽  
Vol 28 (9) ◽  
pp. 1520-1526 ◽  
Author(s):  
Ramesh K. Ramanathan ◽  
Merrill J. Egorin ◽  
Charles Erlichman ◽  
Scot C. Remick ◽  
Suresh S. Ramalingam ◽  
...  
Keyword(s):  
Heat Shock ◽  
Phase Ii ◽  
Mononuclear Cells ◽  
Area Under The Curve ◽  
Heat Shock Protein 90 ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Client Proteins ◽  
Recommended Phase Ii Dose ◽  
Shock Proteins

PurposeTo define the maximum tolerated dose, toxicities, pharmacokinetics, and pharmacodynamics of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17DMAG).Methods17DMAG was given intravenously over 1 hour daily for 5 days (schedule A) or daily for 3 days (schedule B) every 3 weeks. Plasma 17DMAG concentrations were measured by liquid chromatography/mass spectrometry. Heat-shock proteins (HSPs) and client proteins were evaluated at baseline and after treatment on day 1 in peripheral blood mononuclear cells (PBMCs) and in pre- and post-treatment (24 hours) biopsies done during cycle 1 at the recommended phase II dose (n = 7).ResultsFifty-six patients were entered: 26 on schedule A; 30 on schedule B. The recommended phase II doses for schedules A and B were 16 mg/m2and 25 mg/m2, respectively. Grade 3/4 toxicities included liver function test elevation (14%), pneumonitis (9%), diarrhea (4%), nausea (4%), fatigue (4%) and thrombocytopenia (4%). There were no objective responses. Four patients had stable disease. 17DMAG half-life was 24 ± 15 hours. 17DMAG area under the curve (range, 0.7 to 14.7 mg/mL × h) increased linearly with dose. The median HSP90, HSP70, and integrin-linked kinase levels were 87.5% (n = 14), 124% (n = 20), and 99.5% (n = 20) of baseline. Changes in HSPs and client proteins in tumor biopsies were not consistent between baseline and 24 hours nor did they change in the same direction as those in PBMCs collected at the time of biopsy.ConclusionThe recommended phase II doses of 17DMAG (16 mg/m2× 5 days or 25 mg/m2× 3 days, every 3 weeks) are well tolerated and suitable for further evaluation.

scholarly journals Heat-induced expression of albumin during early stages of rat embryo development.

1987 ◽  
Vol 7 (12) ◽  
pp. 4599-4602 ◽  
Author(s):  
U K Srinivas ◽  
C J Revathi ◽  
M R Das
Keyword(s):  
Gene Expression ◽  
Heat Shock ◽  
Embryonic Liver ◽  
Rat Embryo ◽  
Adult Liver ◽  
Stages Of Development ◽  
Induced Expression ◽  
Molecular Events ◽  
Internal Change ◽  
Shock Proteins

An examination of heat-induced expression of proteins in tissues from adult and embryonic liver in rats shows that albumin, which is constitutively expressed in adult liver and is not synthesized in embryos before 16 days of gestation, appears in liver cells at earlier stages of development upon heat shock. On the basis of available evidence for the expression of heat shock proteins at distinct stages of development and on the basis of our findings, it may be argued that there could be common molecular events taking place during development and as a result of heat shock. We suggest also that one of the consequences of heat shock could be an internal change of pH within the cell which, in turn, might trigger alterations in gene expression.

scholarly journals Disaggregases, molecular chaperones that resolubilize protein aggregates

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1273-1292 ◽  
Author(s):  
David Z. Mokry ◽  
Josielle Abrahão ◽  
Carlos H.I. Ramos
Keyword(s):  
Heat Shock ◽  
Molecular Chaperones ◽  
Protein Function ◽  
Protein Aggregates ◽  
Cell Physiology ◽  
Biological Processes ◽  
Loss Of Function ◽  
Prion Propagation ◽  
Shock Proteins

The process of folding is a seminal event in the life of a protein, as it is essential for proper protein function and therefore cell physiology. Inappropriate folding, or misfolding, can not only lead to loss of function, but also to the formation of protein aggregates, an insoluble association of polypeptides that harm cell physiology, either by themselves or in the process of formation. Several biological processes have evolved to prevent and eliminate the existence of non-functional and amyloidogenic aggregates, as they are associated with several human pathologies. Molecular chaperones and heat shock proteins are specialized in controlling the quality of the proteins in the cell, specifically by aiding proper folding, and dissolution and clearance of already formed protein aggregates. The latter is a function of disaggregases, mainly represented by the ClpB/Hsp104 subfamily of molecular chaperones, that are ubiquitous in all organisms but, surprisingly, have no orthologs in the cytosol of metazoan cells. This review aims to describe the characteristics of disaggregases and to discuss the function of yeast Hsp104, a disaggregase that is also involved in prion propagation and inheritance.

scholarly journals AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation

2020 ◽  
Author(s):  
Wen-Cheng Lu ◽  
Ramsey Omari ◽  
Haimanti Ray ◽  
Richard L. Carpenter
Keyword(s):  
Heat Shock ◽  
Functional Role ◽  
Transcriptional Activity ◽  
Heat Shock Factor 1 ◽  
Heat Stress Response ◽  
Subsequent Investigation ◽  
Important Regulator ◽  
Shock Proteins ◽  
Hsf1 Gene

AbstractThe heat stress response activates the transcription factor heat shock factor 1 (HSF1), which subsequently upregulates heat shock proteins to maintain the integrity of the proteome. HSF1 activity requires nuclear localization, trimerization, DNA binding, phosphorylation, and gene transactivation. Phosphorylation at S326 is an important regulator of HSF1 transcriptional activity. Phosphorylation at S326 is mediated by AKT1, mTOR, p38, and MEK1. mTOR, p38, and MEK1 all phosphorylated S326 but AKT1 was the more potent activator. Mass spectrometry showed that AKT1 phosphorylated HSF1 at T142, S230, and T527 in addition to S326 whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326, and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. This study suggests that HSF1 activity is regulated by phosphorylation at specific residues that promote different stages of HSF1 activation. Furthermore, this is the first study to identify the functional role of these phosphorylation events.

scholarly journals Platelet Adhesion to Collagen Under Flow Causes Dissociation of a Phosphoprotein Complex of Heat-Shock Proteins and Protein Phosphatase 1

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1516-1526 ◽  
Author(s):  
Renata Polanowska-Grabowska ◽  
Carl G. Simon ◽  
Rocco Falchetto ◽  
Jeffrey Shabanowitz ◽  
Donald F. Hunt ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Platelet Adhesion ◽  
Blood Platelets ◽  
Protein Phosphatases ◽  
Heat Shock Protein 90 ◽  
Significant Inhibition ◽  
Regulatory Subunit ◽  
Shock Proteins ◽  
Induced Aggregation

Phosphorylation/dephosphorylation events in human blood platelets were investigated during their adhesion to collagen under flow conditions. Using 32P-labeled platelets and one-dimensional gel electrophoresis, we found that adhesion to collagen mediated primarily by the α2β1 integrin resulted in a strong dephosphorylation of several protein bands. Neither adhesion to polylysine nor thrombin-induced aggregation caused similar protein dephosphorylation. In addition, treatment with okadaic acid (OA), an inhibitor of serine/threonine protein phosphatases type 1 (PP1) and 2A (PP2A), caused significant inhibition of adhesion, suggesting that adhesion is regulated by OA-sensitive phosphatases. Recent studies indicate that phosphatases may be associated with the heat-shock proteins. Immunoprecipitations with antibodies against either the heat-shock cognate protein 70 (hsc70) or heat-shock protein 90 (hsp90) showed the presence of a phosphoprotein complex in 32P-labeled, resting human platelets. Antibody probing of this complex detected hsc70, hsp90, two isoforms of the catalytic subunit of PP1, PP1Cα and PP1Cδ, as well as the M regulatory subunit of PP1 (PP1M). OA, at concentrations that markedly blocked platelet adhesion to collagen, caused hyperphosphorylation of the hsc70 complex. In platelets adhering to collagen, hsc70 was completely dephosphorylated and hsp90, PP1α, and PP1M were dissociated from the complex, suggesting involvement of heat-shock proteins and protein phosphatases in platelet adhesion.

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