A Small Molecule Inhibitor of ATPase Activity of HSP70 Induces Apoptosis and Has Antitumor Activities

Ko, Sung-Kyun; Kim, Jiyeon; Na, Deuk Chae; Park, Sookil; Park, Seong‐Hyun; Hyun, Ji Young; Baek, Kyung Hwa; Kim, Nam Doo; Kim, Nak Kyoon; Park, Young Nyun; Song, Kiwon; Shin, Injae

doi:10.1016/j.chembiol.2015.02.004

Cited by 93 publications

(71 citation statements)

References 55 publications

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“…This group found that Az induced cancer cell death by inhibiting HSP-70 and activating caspase dependent apoptosis [26]. Functionally, HSP-70 transports TFAM a major stimulator of mitochondrial activity and is found upregulated in cancer cells.…”

Section: Mitochondrial Transcription Factor a (Tfam)mentioning

confidence: 99%

Mitochondrial pathways to cardiac recovery: TFAM

2016

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Mitochondrial dysfunction underlines a multitude of pathologies; however, studies are scarce that rescue the mitochondria for cellular resuscitation. Exploration into the protective role of mitochondrial Transcription factor A (TFAM) and its mitochondrial functions respective to cardiomyocyte death are in need of further investigation. TFAM is a gene regulator that acts to mitigate calcium mishandling and ROS production by wrapping around mitochondrial DNA (mtDNA) complexes. TFAM’s regulatory functions over serca2a, NFAT and Lon protease contribute to cardiomyocyte stability. Calcium and ROS dependent proteases, calpains and matrix metallo-proteinases (MMP’s) are abundantly found upregulated in the failing heart. TFAM’s regulatory role over ROS production and calcium mishandling leads to further investigation into the cardioprotective role of exogenous TFAM. In an effort to restabilize physiological and contractile activity of cardiomyocytes in HF models, we propose that TFAM-packed exosomes (TFAM-PE) will act therapeutically by mitigating mitochondrial dysfunction. Notably, this is the first mention of exosomal delivery of transcription factors in the literature. Here we elucidate the role of TFAM in mitochondrial rescue and focus on its therapeutic potential.

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Section: Mitochondrial Transcription Factor a (Tfam)mentioning

confidence: 99%

Mitochondrial pathways to cardiac recovery: TFAM

2016

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“…A solid-support immobilized apoptozole was used to pinpoint HSP70 as the potential target of apoptozole in cells; the full-length protein and the ATPase domain bound to the resin, but the SBD did not. Mechanistic studies showed that apoptozole blocks the interaction of HSP70 with APAF-1 (apoptotic peptidase activating factor 1) without interfering with its binding to ASK1 (apoptosis signal-regulating kinase 1), JNK (c-Jun N-terminal kinase), BAX and AIF (apoptosis-inducing factor) (Ko et al, 2015). It restored the chloride channel activity of mutant cystic fibrosis transmembrane conductance regulator (CFTR) by promoting its membrane trafficking, suggesting its potential use, when utilized in concert with complementary methods, as a tool to dissect disease mechanism associated with cystic fibrosis (Cho et al, 2011).…”

Section: Hsp70 Probesmentioning

confidence: 99%

Chemical Tools to Investigate Mechanisms Associated with HSP90 and HSP70 in Disease

Shrestha

Patel

Chiosis

2016

Cell Chemical Biology

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The chaperome is a large and diverse protein machinery composed of chaperone proteins and a variety of helpers, such as the co-chaperones, folding enzymes and scaffolding and adapter proteins. Heat shock protein 90s and 70s (HSP90s and HSP70s), the most abundant chaperome members in human cells, are also the most complex. As we have learned to appreciate, their functions are context dependent and manifested through a variety of conformations that each recruit a subset of co-chaperone, scaffolding and folding proteins and which are further diversified by the post-translational modifications each carry, making their study through classic genetic and biochemical techniques quite a challenge. Chemical biology tools and techniques have been developed over the years to help decipher the complexities of the HSPs and this review will provide an overview of such efforts with focus on HSP90 and HSP70.

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“…The highly conserved HSP70/HSC70 share approximately 90% identical sequences in the N-terminus nucleotide binding domain (NBD), but not in the C-terminus substrate binding domain (SBD)20. The affinity of SBD to substrate is strictly regulated by NBD through conformational changes induced by the hydrolysis of ATP to ADP21. The ADP-binding state exhibits a higher affinity to substrate than the ATP-binding state21.…”

mentioning

confidence: 99%

“…The affinity of SBD to substrate is strictly regulated by NBD through conformational changes induced by the hydrolysis of ATP to ADP21. The ADP-binding state exhibits a higher affinity to substrate than the ATP-binding state21. Modulating the switch between the ATP- and ADP-binding states controls the chaperone function of HSP70/HSC7021.…”

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confidence: 99%

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Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70

Wang

Lam

Chen

et al. 2016

Sci Rep

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Tylophorine analog DCB-3503 is a potential anticancer and immunosuppressive agent that suppresses the translation of cellular regulatory proteins, including cyclin D1, at the elongation step. However, the molecular mechanism underlying this phenomenon remains unknown. This study demonstrates that DCB-3503 preferentially binds to heat shock cognate protein 70 (HSC70), which is a determinant for cyclin D1 translation by binding to the 3′-untranslated region (3′ UTR) of its mRNA. DCB-3503 allosterically regulates the ATPase and chaperone activities of HSC70 by promoting ATP hydrolysis in the presence of specific RNA binding motifs (AUUUA) of cyclin D1 mRNA. The suppression of cyclin D1 translation by DCB-3503 is not solely caused by perturbation of the homeostasis of microRNAs, although the microRNA processing complex is dissociated with DCB-3503 treatment. This study highlights a novel regulatory mechanism of protein translation with AUUUA motifs in the 3′ UTR of mRNA by HSC70, and its activity can be allosterically modulated by DCB-3503. DCB-3503 may be used to treat malignancies, such as hepatocellular carcinoma or breast cancer with elevated expression of cyclin D1.

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A Small Molecule Inhibitor of ATPase Activity of HSP70 Induces Apoptosis and Has Antitumor Activities

Cited by 93 publications

References 55 publications

Mitochondrial pathways to cardiac recovery: TFAM

Mitochondrial pathways to cardiac recovery: TFAM

Chemical Tools to Investigate Mechanisms Associated with HSP90 and HSP70 in Disease

Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70

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