Molecular Targets Other than BCR-ABL: How to Incorporate them into the CML Therapy?
Jorge Cortes, Michael Deininger in Chronic Myeloid Leukemia, 2006
Heat-shock protein 90 (Hsp90) has recently emerged as an attractive molecular target for the therapy of CML. Hsp90 functions as a molecular chaperone which interacts with “client” proteins including Raf, Akt, FLT-3, and Bcr-Abl (1). Interaction with Hsp90 is essential for maintaining the client proteins in a stable and functional conformation and requires binding of adenosine triphosphate (ATP) to the hydrophobic N-terminal pocket of Hsp90. Benzoquinone ansamycins such as geldanamycin and its less toxic derivative, 17-allylamino-17-demethoxygeldana-mycin (17-AAG) (both from the National Cancer Institute, Bethesda, Maryland, U.S.A.) bind to the ATP-binding pocket of Hsp90, thereby inhibiting its ability to function as a chaperone(2). The moment the interaction between Hsp90 and its client protein has been disrupted, another chaperone, heat-shock protein 70 (Hsp70), is recruited. Hsp70 has the opposite function to Hsp90 and the interaction of this chaperone with the client protein leading to its polyubiquitinylation and degradation by the 26S proteasome(1). In vitro treatment of CML cell lines with geldanamycin and 17-AAG leads to the down regulation of p210Bcr-Abl protein and induces cell death by apoptosis(3,4).
The Stress Response and Stress Proteins
John J. Lemasters, Constance Oliver in Cell Biology of Trauma, 2020
A key element in this regulatory system is the HSF (heat shock factor) family of transcription factors. In unstressed cells of most eukaryotes, HSF exists as a monomer in the cytoplasm. Upon stress, HSF trimerizes, migrates to the nucleus, and binds to consensus sequences (HSEs, or heat shock elements) in the promoters of the heat-shock genes, thereby relieving the block to transcription. HSEs occur in the promoters of heat-shock genes, including those for hsp70. However, hsp70 is exceptional in that it, either by itself or in combination with other factors, may inhibit HSF-activated transcription in at least two ways: First, it may interact with unbound HSF to inhibit or reverse trimerization. Second, it may interact with HSF trimers bound to HSE, either promoting their dissociation from HSE or otherwise inhibiting their activation of transcription. In any event, hsp70 is a protein that apparently interacts with its own transcription factor to inhibit its own synthesis (and, in so doing, coordinately regulates the expression of other stress proteins). Unfolded proteins apparently compete with HSF monomer for interaction with hsp70. Thus, as unfolded proteins bind hsp70 and thereby derepress HSF activation of transcription, they set the stage for their own rescue or demise. DnaK, the hsp70 homologue of E. coli, plays a similar role in the autoregulation of the stress response in this organism. Several publications provide more detailed entree to this topic.32,33
Responses to Muscular Exercise, Heat Shock Proteins as Regulators of Inflammation, and Mitochondrial Quality Control
Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse in The Routledge Handbook on Biochemistry of Exercise, 2020
HSPs are critical in cell proteostasis through their ability to fold nascent proteins and refold damaged proteins. Importantly, HSP70, HSP40, and HSP90 are all critical in ensuring proteostasis by facilitating proper folding of newly translated proteins exiting ribosomes at the endoplasmic reticulum (ER) (24, 29, 92). Ribosome-associated co-chaperones (MPP1 and HSPA14) transfer nascent proteins to non-ribosomal HSP70 chaperone complexes (HSP70 and HSP40), which facilitate the native folding of proteins requiring a high degree of complex co-translational folding (some subsets may be transferred to HSP90 for further processing via Hsp70-Hsp90 Organizing Protein (HOP)) (88, 92). In addition to the folding of nascent proteins, these HSPs are involved in the refolding of damaged or unfolded proteins. After recognition, recruitment, and transfer of unfolded proteins via co-chaperone HSP40, protein-bound HSP70 undergoes adenosine triphosphate (ATP) cycling via nucleotide exchange factors to cause conformational changes in HSP70—ultimately enabling native folding based on amino acid characteristics (i.e., polarity) (29). If proteins are unable to refold via HSP70, they can be passed along to chaperonins (i.e., HSP60 and HSP10) and/or HSP90 for extended processing. If it is not possible for the protein to fold into its native form via its interactions with these chaperones, it is likely to be tagged for degradation via the ubiquitin–proteasome system (UPS).
Hsp70 modulates immune response in pancreatic cancer through dendritic cells
Published in OncoImmunology, 2021
Bhuwan Giri, Prateek Sharma, Tejeshwar Jain, Anthony Ferrantella, Utpreksha Vaish, Siddharth Mehra, Bharti Garg, Srikanth Iyer, Vrishketan Sethi, Zoe Malchiodi, Rossana Signorelli, Harrys K.C Jacob, John George, Preeti Sahay, Ejas P. Bava, Rajinder Dawra, Sundaram Ramakrishnan, Ashok Saluja, Vikas Dudeja
Heat shock proteins are part of an evolutionarily conserved cellular machinery, which are geared toward protecting cells and tissues from various stresses, including thermal distress.11 Heat Shock Protein 70, or Hsp70, is a member of heat shock protein family, which is ubiquitously expressed in a variety of cell types.12 We have previously demonstrated that Hsp70 is overexpressed in pancreatic cancer cells and that it plays a prosurvival and antiapoptotic role in pancreatic cancer epithelial cells. However, the role of Hsp70 in the TME is unknown.13 In the current study, we have investigated the role of Hsp70 in TME in the progression of cancer. Our results suggest that selective genetic deletion of Hsp70 in the TME significantly attenuates tumor growth. Our results also suggest that this effect is due to the deletion of Hsp70 in immune cellsand not due to depletion of Hsp70 in CAFs. Using a combination of in vitro and in vivo approaches, we demonstrate that lack of Hsp70 in dendritic cells energizes the antigen presentation machinery, which, in turn, leads to the development of a robust anticancer immune response. These findings pave the way for a more complete understanding in modulating and designing effective therapeutic approaches that can complement immunotherapy and dendritic cell vaccination against pancreatic cancer.
The enigma of headaches associated with electromagnetic hyperfrequencies: Hypotheses supporting non-psychogenic algogenic processes
Published in Electromagnetic Biology and Medicine, 2020
DH Toffa, AD Sow
Non-thermal HF exposure may induce metabolic level disturbances resulting in cell quiescence or, on the contrary, hyperexcitability. Campisi et al. (2010) exposed primary rat neocortical-differentiated astroglial cell cultures of 14 d in vitro for 5, 10, or 20 min to either 900 MHz continuous waves or 900 MHz modulated waves (sinusoidal waveform at 50 Hz and 100% modulation index) (Campisi et al. 2010). The SAR was not mentioned, but the RMS value was 10 V/m. Although they used non-thermal conditions, they observed a significant increase in ROS levels and DNA fragmentation after a short exposure of the astrocytes to modulated HF for 20 min. Moreover, an increase in HSP70 heat shock proteins had been reported by Deshmukh and al. (Deshmukh et al. 2016, 2015). In a first study, they exposed male Fischer rats to low-intensity HF (900, 1800 MHz, and 2450 MHz; SAR of 0.5953 × 10−3, 0.5835 × 10−3, and 0.6672 × 10−3, respectively) versus sham-conditions for 180 d. The HF exposure resulted in brain elevated HSP70 levels and DNA damage (Deshmukh et al. 2015). In a subsequent study, they exposed the male Fischer rats to subchronic HF-irradiation (SAR of 5.953 × 104 W/kg) for 90 d with sham exposure, 900, 1800, and 2450 MHz (Deshmukh et al. 2016). Then, authors observed that irradiation at 900–2450 MHz leads to a decline in cognitive function, an increase in HSP70 level and DNA damage in brain. Such anomalies may be responsible for sublethal or lethal metabolic alterations of neurons or glial cells (Campisi et al. 2010).
High altitude hypoxia on brain ultrastructure of rats and Hsp70 expression changes
Published in British Journal of Neurosurgery, 2019
Wen-Hua Li, Yu-Xiang Li, Jun Ren
Heat shock response is a kind of cellular level biological response to stress. Since heat shock response was found by Tissiéres et al.1 in the study on Drosophila larvae in 1974; heat shock response has become a hot research topic in various fields. The product of heat shock response was heat shock protein (HSP), while the first gene to be cloned and identified was HSP70. The human HSP70 gene is located in chromosome 1, 5, 6, 9, 11 and 14; and also considered to be present in chromosome 21.2,3 Their common code of a set of relative molecular mass from 66,000 to 78,000 was highly related to the protein. HSP70 gene family members can be used as a molecular chaperone to promote the correct folding, assembly and transport of new synthetic proteins, and promote the re-folding or degradation of proteins4,5. HSP70 protein plays an important protective role in the formation of heat tolerance or poison tolerance, as well as the prevention of oxidative damage. Heat stress protein is very important for the stability and adaptability of the intracellular environment. It is known that nucleotide substitution, deletion or insertion mutations can adjust the start of function or transcriptional activity6, while different HSP70 expression levels can modulate stress, or disease susceptibility or tolerance.7 Therefore, this study aimed to observe changes in brain tissue and HSP70 expression in high-altitude hypoxia rats, in order to clarify the mechanism of HSP70 in high-altitude hypoxia adaptation.
Related Knowledge Centers
- Atpase
- Conserved Sequence
- Protein Domain
- Protein Folding
- Stress
- Toxicity
- Protein Family
- Heat Shock Protein
- N-Terminus
- Adenosine Triphosphate