Hsp90α and Hsp90β Co-Operate a Stress-Response Mechanism to Cope With Hypoxia and Nutrient Paucity during Wound Healing

Jayaprakash, Priyamvada; Dong, Hangming; Zou, Mengchen; Bhatia, Ayesha; O’Brien, Kathryn; Chen, Mei; Woodley, David T.; Li, Wei

doi:10.1242/jcs.166363

Cited by 67 publications

(48 citation statements)

References 30 publications

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“…An increased level of thioredoxin was also observed presumably to control the redox state of the cells [88]. HSP27 is increased in dry skin, but we observed HSP90a to be decreased in our samples indicating that there may be reduced cell mobility [89]. HSP701A levels are higher in darker skin phenotypes and our increases may be related to an increased tanning response on the cheeks [90].…”

Section: Discussionmentioning

confidence: 53%

The effect of photodamage on the female Caucasian facial stratum corneum corneome using mass spectrometry‐based proteomics

Voegeli

Monneuse²,

Schoop

et al. 2017

Intern J of Cosmetic Sci

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BACKGROUND:The effect of photodamage on facial stratum corneum (SC) is still poorly understood. OBJECTIVE: To describe the SC proteome from tape strippings of Caucasian SC from photoexposed cheek and photoprotected postauricular (PA) site, a global analysis of photodamage on the skin will be developed leading to a better understanding of keratinocyte signalling pathways and identification of new molecular targets for the treatment of photoaged skin. METHODS: Female Caucasian subjects had nine consecutive tape strippings taken from their cheeks and PA site. Proteins were extracted and the trypsin-digested peptides were analysed by nanochromatography coupled to a high-resolution mass spectrometer. Data-dependent acquisition allowed protein identification that was processed by Paragon algorithm of Protein Pilot software. RESULTS: Changes in the levels of epidermal differentiation proteins were apparent indicating poor epidermal differentiation and SC maturation (keratins, cornified envelope (CE) proteins) on photoexposed cheeks. Differences in protease-anti-protease balance were observed for corneodesmolysis (favouring desquamation) and filaggrinolysis (favouring reduced filaggrin processing). 12R-LOX, a CE maturation enzyme, was reduced in photodamaged skin but not transglutaminases. Changes in signal keratinocyte transduction pathway markers were demonstrated especially by reduced levels of downstream signalling markers such as calreticulin (unfolded protein response; UPR) and increased level of stratifin (target of rapamycin; mTOR). Evidence for impaired proteostasis was apparent by reduced levels of a key proteasomal subunit (subunit beta type-6). Finally, key antioxidant proteins were upregulated except catalase. CONCLUSION: Clear examples of poor keratinocyte differentiation and associated metabolic and signalling pathways together with reduced SC maturation were identified in photodamaged facial SC. Corneocyte immaturity was evident with changes in CE proteins. Particularly, the reduction in 12R-LOX is a novel finding in photodamaged skin and supports the lack of SC maturation. Moreover, filaggrinolysis was reduced, whereas corneodesmolysis was enhanced. From our results, we propose that there is a poor crosstalk between the keratinocyte endoplasmic reticulum UPR, proteasome network and autophagy machinery that possibly leads to impaired keratinocyte proteostasis. Superimposed on these aberrations is an apparently enhanced mTOR pathway that also contributes to reduced SC formation and maturation. Our results clearly indicate a corneocyte scaffold disorder in photodamaged cheek SC.R esum e CONTEXTE: Les effets des dommages dus a l'exposition a la lumiere sur le stratum corneum (SC) sont encore mal compris. OBJECTIFS: D ecrire le prot eome du SC issu de pr el evements par bandes adh esives provenant de la joue, expos ee a la lumi ere, et de la r egion post-auriculaire, prot eg ee de la lumi ere, de sujets caucasiens.A cette fin, une analyse globale des dommages cutan es dus a l'exposition a la lumi er...

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Section: Discussionmentioning

confidence: 53%

The effect of photodamage on the female Caucasian facial stratum corneum corneome using mass spectrometry‐based proteomics

Voegeli

Monneuse²,

Schoop

et al. 2017

Intern J of Cosmetic Sci

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“…However, chronic hypoxia condition leads to chemo-resistance in cancer and pathogenesis in several organs (42, 60). During hiCMs differentiation, we observed a decreased expression of EP300, HSP90AA1 and HSP90AB1 genes resulting in reduced hypoxic responses and decreased wound healing activity (61). As stable or increased NOS3 protects from chronic hypoxia in embryonic developmental stages (62), decreased NOS3 expression was seen in differentiated cardiomyocytes which leads to apoptosis in these cells (62).…”

Section: Discussionmentioning

confidence: 99%

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Shanmugam

Crossman

Rajasingh

et al. 2019

Preprint

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Background: Reprogramming of somatic cells into pluripotent stem cells (iPSC) and subsequent differentiation into iPSC-derived cardiomyocytes (iCM) seems to be a promising strategy for cardiac regenerative therapy. However, recent failure or poor outcomes in cardiac cell therapy warrants further investigation focusing on the infarction/wound environment (site of healing) to improve the cardiac regenerative medicine. Here, using next generation sequencing (NGS), we analyzed the global transcriptome to discover the unidentified genes/pathways that are crucial for cell survival, cytoprotection and mitochondrial dynamics during the differentiation of iPSC into iCM.Methods: High throughput NGS was performed RNA from human iPSCs and iCMs (n=3/group) and analyzed the global changes in the transcriptome during differentiation. Furthermore, Ingenuity Pathway Analysis (IPA) and Gene Ontology (GO) for biological process were performed to understand the transcriptional networks that are involved during iCM differentiation. RNA-seq data were further validated by qRT-PCR analyses. Results:Global transcriptome analysis revealed that ~9,290 genes (log 2 FC >2) were significantly altered in human iCMs compared to the parent iPSCs, in which 4,784 transcripts were substantially upregulated and 4,506 transcripts were down-regulated during differentiation.GO enrichment and IPA analyses revealed the top 10 regulatory networks (i.e. hierarchical order) involved in differentiation of iCMs including cardiomyocyte remodeling, integrin-linked kinase signaling, Rho family of GTPases, etc. Surprisingly, none of the top 10 pathways listed the genes liable for redox signaling networks that are crucial for the basal cellular redox homeostasis, Nrf2-dependent antioxidant defense, mitochondrial functions and cell survival. Our deeper and unbiased analysis of this data revealed that the genes involved in above canonical signaling pathways are found in the middle of the inverted vertical cone. Of note, although these pathways are significantly altered during the differentiation (of iPS into cardiomyocytes), a majority of them are ranked low in the hierarchical list (>150). Validation of the randomly selected genes representing various pathways real-time qPCR confirmed the global transcriptome changes observed in NGS. Conclusion:We highlight the significance of Nrf2-redox and mitochondrial transcriptome during differentiation of iPSC into iCMs. Thus, targeting the redox signaling mechanisms in iCMs may enhance their efficiency for cell therapy and improved myocardial repair.180 genes were detected out of 230 genes known to constitute this pathway, whereas 58 genes were increased and 56 genes were decreased. From this list, the top 15 up and down-regulated genes were used to generate the heat-maps. A substantial list of genes were downregulated during cardiomyocyte differentiation including, MGST1, GSTM5, PRKCQ, PRKCB and PIK3R, while PIK3R5ACTA2, GSTM3, FMO1, ACTC1 and GSTA3 were increased during cardiomyocyte differentiation. RNA-seq data was valid...

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“…In addition to its immune properties, extracellular Hsp90 plays a remarkably powerful role in stimulating wound healing[95]. As many of the properties of cancer resemble those found in wound healing this suggested a potential role in malignancy.…”

Section: Extracellular Chaperones: the Jokers In The Packmentioning

confidence: 99%

Heat Shock Proteins Promote Cancer: It's a Protection Racket

Calderwood

Gong

2016

Trends in Biochemical Sciences

332

251

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Heat Shock Proteins (HSP) are expressed at high levels in cancer and form a fostering environment essential for tumor development. We have reviewed the recent data in this area, concentrating mainly on Hsp27, Hsp70 and Hsp90. The overriding role of the HSPs in cancer is to stabilize the active functions of overexpressed and mutated cancer gene. Elevated HSPs are thus required for many of the traits that underlie the morbidity of cancer, including increased growth, survival and formation of secondary cancers. In addition, HSPs participate in the evolution of cancer treatment resistance. HSPs are also released from cancer cells and influence malignant properties by receptor- mediated signaling. Current data strongly support efforts to target HSPs in cancer treatment.

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Hsp90α and Hsp90β Co-Operate a Stress-Response Mechanism to Cope With Hypoxia and Nutrient Paucity during Wound Healing

Cited by 67 publications

References 30 publications

The effect of photodamage on the female Caucasian facial stratum corneum corneome using mass spectrometry‐based proteomics

The effect of photodamage on the female Caucasian facial stratum corneum corneome using mass spectrometry‐based proteomics

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Heat Shock Proteins Promote Cancer: It's a Protection Racket

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