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.

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 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.

Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter

2019 ◽  
Vol 109 (4) ◽  
pp. 362-373
Author(s):  
Denis Ciato ◽  
Ran Li ◽  
Jose Luis Monteserin Garcia ◽  
Lilia Papst ◽  
Sarah D’Annunzio ◽  
...  
Keyword(s):  
Heat Shock ◽  
Clinical Features ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Primary Cultures ◽  
Heat Shock Protein 90 ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Promising Treatment ◽  
Acth Secreting

Background: Cushing’s disease (CD) is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. They express high levels of heat shock protein 90 and heat shock factor 1 (HSF1) in comparison to the normal tissue counterpart, indicating activated cellular stress. Aims: Our objectives were: (1) to correlate HSF1 expression with clinical features and hormonal/radiological findings of CD, and (2) to investigate the effects of HSF1 inhibition as a target for CD treatment. Patients/Methods: We examined the expression of total and pSer326HSF1 (marker for its transcriptional activation) by Western blot on eight human CD tumours and compared to the HSF1 status of normal pituitary. We screened a cohort of 45 patients with CD for HSF1 by immunohistochemistry and correlated the HSF1 immunoreactivity score with the available clinical data. We evaluated the effects of HSF1 silencing with RNA interference and the HSF1 inhibitor KRIBB11 in AtT-20 cells and four primary cultures of human corticotroph tumours. Results: We show that HSF1 protein is highly expressed and transcriptionally active in CD tumours in comparison to normal pituitary. The immunoreactivity score for HSF1 did not correlate with the typical clinical features of the disease. HSF1 inhibition reduced proopiomelanocortin (Pomc) transcription in AtT-20 cells. The HSF1 inhibitor KRIBB11 suppressed ACTH synthesis from 75% of human CD tumours in primary cell culture. This inhibitory action on Pomc transcription was mediated by increased glucocorticoid receptor and suppressed Nurr77/Nurr1 and AP-1 transcriptional activities. Conclusions: These data show that HSF1 regulates POMC transcription. Pharmacological targeting of HSF1 may be a promising treatment option for the control of excess ACTH secretion in CD.

scholarly journals A Brain Penetrating Heat-Shock Protein 90 Inhibitor NXD30001 Inhibits Glioblastoma as a Monotherapy or in Combination With Radiation

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Hao Chen ◽  
Jialiang Wang ◽  
Hengli Tian
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Median Survival ◽  
Therapeutic Potential ◽  
Heat Shock Protein 90 ◽  
Tumor Bearing ◽  
Client Proteins

Abstract INTRODUCTION It has been increasingly recognized that glioblastoma multiforme (GBM) is a highly heterogeneous disease, which is initiated and sustained by molecular alterations in an array of signal transduction pathways. Heat-shock protein 90 (Hsp90) is a molecular chaperone to be critically implicated in folding and activation of a diverse group of client proteins, many of which are key regulators of important glioblastoma biology. METHODS To determine the therapeutic potential of targeting Hsp90 in glioblastoma, we assessed the anti-neoplastic efficacy of NXD30001, a brain-penetrating Hsp90 inhibitor as a monotherapy or in combination with radiation, both in Vitro and in Vivo. RESULTS Our results demonstrated that NXD30001 potently inhibited neurosphere formation, growth and survival of CD133 + glioblastoma stem cells (GSCs) with the half maximal inhibitory concentrations (IC50) at low nanomolar concentrations. At suboptimal concentrations, inhibition of Hsp90 did not exert cytotoxic activity but rather increased radiosensitivity in GSCs. CD133- GBM cells were less sensitive and not radiosensitized by NXD30001. In lines with its cytotoxic and radiosensitizing effects, NXD30001 dose-dependently decreased phosphorylation protein levels of multiple Hsp90 client proteins, including those playing key roles in GSCs, such as EGFR, Akt, c-Myc, and Notch1. In addition, combining NXD30001 with radiation could impair DNA damage response and ER stress response to induce apoptosis of GSCs. Treatment of orthotopic glioblastoma tumors with NXD30001 extended median survival of tumor-bearing mice by approximately 20% (treated 37 days vs vehicle 31 d, P = .0026). Radiation alone increased median survival of tumor-bearing mice from 31 to 38 d, combination with NXD30001 further extended survival to 43 d (P = .0089). CONCLUSION Our results suggest that GBM stem cells (CD133+) are more sensitive to NXD30001 than non-stem GBM cells (CD133-). Furthermore, combination NXD30001 with radiation significantly inhibits GBM progression than use it as a monotherapy by targeting GSCs.

Pharmacodynamics and pharmacokinetics of AUY922 in a phase I study of solid tumor patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3533-3533
Author(s):  
S. Ide ◽  
M. Motwani ◽  
M. R. Jensen ◽  
J. Wang ◽  
N. Huseinovic ◽  
...  
Keyword(s):  
Heat Shock ◽  
Phase I ◽  
Single Agent ◽  
Xenograft Model ◽  
Heat Shock Protein 90 ◽  
Post Treatment ◽  
Multiple Time ◽  
Heat Shock Factor 1 ◽  
Multiple Time Points ◽  
Hsp70 Induction

3533 Background: AUY922 is a synthetic inhibitor of Heat Shock Protein 90. Disruption of the HSP90 chaperone hetero- complex results in the loss of repression of heat shock factor-1 (HSF1), and subsequent induction of HSP70. We evaluated HSP70 as a pharmacodynamic (PD) marker of AUY922 activity in a phase I/II clinical trial in patients (pts) with solid tumors. Methods: Single agent AUY922 was administered by IV infusion once a week to pts with advanced solid malignancies. HSP70 levels in PBMC were quantitated by ELISA in samples taken at baseline and multiple time-points post the 1st and 5th treatments over two cycles. Fold change of HSP70 induction was calculated and compared to dose level and AUY922 blood exposure obtained within the first week of treatment (single dose) at 6, 24, 48, and 168 hours post-treatment. Results: Of the 40 pts treated to date, HSP70 levels in PBMC has been evaluated in 36, encompassing seven dose levels ranging from 2 mg/m2 to 40mg/m2. Baseline levels of HSP70 in PBMC ranged from 26.0 to 95.1 ng/mg protein, with a median of 42.5ng/mg. The highest level of HSP70 induction obtained over two cycles was increasing with dose from 2 to 40 mg/m2, with a range of 1.4 to 12.1 fold, and the amount of HSP70 induction was frequently higher in the second cycle of treatment. In the first cycle of treatment, HSP70 induction is correlated to blood AUC. The degree of HSP70 upregulation in PBMCs at 40 mg/m2 exceeds the 8-fold upregulation seen in BT474 xenograft tumor tissue when treated with efficacious doses of AUY922. Conclusions: PK/PD analyses show that the highest level of HSP70 achieved post-treatment increases with dose, and at the highest dose tested thus far (40mg/m2), this pharmacodynamic effect has not yet reached a maximum response. Additionally, our analysis suggests that in humans, the PD effect of AUY922 is reaching the level corresponding to that required for anti-tumor effect in the BT474 xenograft model. [Table: see text]

Phase Ib study of heat shock protein 90 inhibitor, onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS1127-TPS1127
Author(s):  
Robert Wesolowski ◽  
Maryam B. Lustberg ◽  
Raquel E. Reinbolt ◽  
Jeffrey Bryan VanDeusen ◽  
Sagar D. Sardesai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Standard Dose ◽  
Heat Shock Protein 90 ◽  
Mapk Signaling ◽  
Amino Terminal ◽  
Client Proteins

TPS1127 Background: Heat shock protein 90 (HSP90) is a molecular chaperone which is necessary for proper folding and stabilization of proteins. Client proteins of HSP90 include many oncogenic proteins known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathway and androgen receptor. High expression of HSP90 in breast cancer has been associated with poor outcome. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM. Methods: Patients with inoperable or metastatic, triple negative or < 10% hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel is administered alone. The primary objective of the study is to determine recommended phase II dose and assess the toxicity profile of the combination. The secondary objectives include pharmacokinetic of each agent. Overall response rate, response duration and progression-free survival will also be assessed. The study is currently enrolling patients to dose level 2. Clinical trial information: NCT02474173. [Table: see text]

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