The small heat shock protein, HSP30, is associated with aggresome-like inclusion bodies in proteasomal inhibitor-, arsenite-, and cadmium-treated Xenopus kidney cells

Khan, Saad; Khamis, Imran; Heikkila, John J.

doi:10.1016/j.cbpa.2015.07.022

Cited by 12 publications

(14 citation statements)

References 94 publications

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“…4b). Similar observations have been made in vertebrate systems, including human skeletal muscle as well as in bacteria [198][199][200] . The recruitment of these chaperones into the insoluble fraction may reflect a controlled attempt of the organism to sequester protein aggregates, consistent with age-dependent formation of aggregates (as inclusion bodies) being a regulated, protective response to lower the pressure on the proteostasis network 166 .…”

Section: Controlled Protein Aggregationsupporting

confidence: 81%

The proteostasis network and its decline in ageing

Hipp

Kasturi

2019

Nat Rev Mol Cell Biol

1,081

866

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Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones as well as proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects in particular postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform on strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan.

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Section: Controlled Protein Aggregationsupporting

confidence: 81%

The proteostasis network and its decline in ageing

Hipp

Kasturi

2019

Nat Rev Mol Cell Biol

1,081

866

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“…Anticancer activity of Withania somnifera, has been assigned to Wi-A and Wi-N by a large number of independent studies that revealed their multiple targets and modes of action [4,7,9,[65][66][67][68]. Furthermore, whereas Wi-A, by itself, caused toxicity to normal cells [7]; acute toxicity and pharmacokinetics studies revealed that in vivo oral administration of Wi-A in Ehrlich ascites carcinoma swiss mice model produces severe toxicity effects like diarrhea, weight loss and mortality above 70 mg/kg BW [69].…”

Section: Discussionmentioning

confidence: 99%

Combination of Withaferin-A and CAPE Provides Superior Anticancer Potency: Bioinformatics and Experimental Evidence to Their Molecular Targets and Mechanism of Action

Sari

Bhargava

Dhanjal

et al. 2020

Cancers

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We have earlier reported anticancer activity in Withaferin A (Wi-A), a withanolide derived from Ashwagandha (Withania somnifera) and caffeic acid phenethyl ester (CAPE), an active compound from New Zealand honeybee propolis. Whereas Wi-A was cytotoxic to both cancer and normal cells, CAPE has been shown to cause selective death of cancer cells. In the present study, we investigated the efficacy of Wi-A, CAPE, and their combination to ovarian and cervical cancer cells. Both Wi-A and CAPE were seen to activate tumor suppressor protein p53 by downregulation of mortalin and abrogation of its interactions with p53. Downregulation of mortalin translated to compromised mitochondria integrity and function that affected poly ADP-ribose polymerase1 (PARP1); a key regulator of DNA repair and protein-target for Olaparib, drugs clinically used for treatment of breast, ovarian and cervical cancers)-mediated DNA repair yielding growth arrest or apoptosis. Furthermore, we also compared the docking capability of Wi-A and CAPE to PARP1 and found that both of these could bind to the catalytic domain of PARP1, similar to Olaparib. We provide experimental evidences that (i) Wi-A and CAPE cause inactivation of PARP1-mediated DNA repair leading to accumulation of DNA damage and activation of apoptosis signaling by multiple ways, and (ii) a combination of Wi-A and CAPE offers selective toxicity and better potency to cancer cells.

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“…Also, increased levels of HSPB6 were reported in dog and rat heart due to congestive heart failure or exercise and also in rat bladder in response to partial urethral ligation (Batts et al, 2006;Boluyt et al, 2006;Dohke et al, 2006). While the mechanism(s) associated with the increase in X. laevis HSPB6 levels in response to cadmium or MG132 is unclear, it is likely that their enhanced levels may be due, at least in part, to a reduction in HSPB6 degradation since both cadmium and MG132 were found to inhibit the ubiquitin-proteasome system in Xenopus A6 cells (Young and Heikkila, 2010;Brunt et al, 2012;Khan et al, 2012;Khamis and Heikkila, 2013;Khan et al, 2015).…”

Section: Discussionmentioning

confidence: 97%

“…The only study to date involving poikilothermic vertebrates was a report indicating that zebrafish HSPB6 mRNA was expressed constitutively at low levels in early embryos and that it was not upregulated by heat shock (Marvin et al, 2008). Xenopus laevis, the South African clawed frog, has been used as a model system in our laboratory to examine the accumulation, properties and chaperone function of the sHSPs HSP30 and HSP27 (Krone et al, 1992;Lang et al, 1999;Fernando and Heikkila, 2000;Abdulle et al, 2002;Fernando et al, 2002;Tuttle et al, 2007;Woolfson and Heikkila, 2009;Heikkila, 2010;Brunt et al, 2012;Khamis and Heikkila, 2013;Khan and Heikkila, 2014;Khan et al, 2015). In the current study, we present an examination of the various domains and phylogenetic relationships of the putative amino acid sequence of X. laevis HSPB6 as well as its ability to act as a molecular chaperone by inhibiting heat-induced aggregation of client protein.…”

Section: Introductionmentioning

confidence: 99%