ERK8 is a novel HuR kinase that regulates tumour suppressor PDCD4 through a miR-21 dependent mechanism

Liwak-Muir, Urszula; Dobson, Christine C.; Naing, Thet; Wylie, Quinlan; Chehadé, Lucia; Baird, Stephen; Chakraborty, Pranesh; Holčı́k, Martin

doi:10.18632/oncotarget.6363

Cited by 25 publications

(20 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, pretreatment of CMs with stressed CPC-derived exosomes (or miR-21 mimic) rescued the decrease of miR-21 and exhibited decreased apoptosis when exposed to oxidative stress [ 43 ]. These findings support the antiapoptotic role of miR-21 in cytoprotection, which further studies revealed to occur by directly targeting PDCD4—a promoter of tumor cell apoptosis [ 81 ]. Similarly, exosomes isolated from mouse CPCs which demonstrated protection against oxidative stress-induced apoptosis were found to be enriched in miR-451/−144 [ 82 ].…”

Section: Exosomes and Mirnassupporting

confidence: 71%

Potential Role of Exosomes in Mending a Broken Heart: Nanoshuttles Propelling Future Clinical Therapeutics Forward

Dougherty

Mergaye

Kumar

et al. 2017

Stem Cells International

View full text Add to dashboard Cite

Stem cell transplantation therapy is a promising adjunct for regenerating damaged heart tissue; however, only modest improvements in cardiac function have been observed due to poor survival of transplanted cells in the ischemic heart. Therefore, there remains an unmet need for therapies that can aid in attenuating cardiac damage. Recent studies have demonstrated that exosomes released by stem cells could serve as a potential cell-free therapeutic for cardiac repair. These exosomes/nanoshuttles, once thought to be merely a method of waste disposal, have been shown to play a crucial role in physiological functions including short- and long-distance intercellular communication. In this review, we have summarized studies demonstrating the potential role of exosomes in improving cardiac function, attenuating cardiac fibrosis, stimulating angiogenesis, and modulating miRNA expression. Furthermore, exosomes carry an important cargo of miRNAs and proteins that could play an important role as a diagnostic marker for cardiovascular disease post-myocardial infarction. Although there is promising evidence from preclinical studies that exosomes released by stem cells could serve as a potential cell-free therapeutic for myocardial repair, there are several challenges that need to be addressed before exosomes could be fully utilized as off-the-shelf therapeutics for cardiac repair.

show abstract

Section: Exosomes and Mirnassupporting

confidence: 71%

Potential Role of Exosomes in Mending a Broken Heart: Nanoshuttles Propelling Future Clinical Therapeutics Forward

Dougherty

Mergaye

Kumar

et al. 2017

Stem Cells International

View full text Add to dashboard Cite

show abstract

“…PDCD4, PTEN, RECK and Bcl-2 can be regulated by miR-21 in many cell types. These genes are critical for promoting cell proliferation, differentiation and migration[ 63 – 65 ]. PTEN has been reported to be a target gene of miR-21 in many cell types[ 3 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cell-derived exosomal miR-21 protects C-kit+ cardiac stem cells from oxidative injury through the PTEN/PI3K/Akt axis

Shi¹,

Wang²,

Zhao³

et al. 2018

PLoS ONE

View full text Add to dashboard Cite

Stem cell (SC) therapy for ischemic cardiomyopathy is hampered by poor survival of the implanted cells. Recently, SC-derived exosomes have been shown to facilitate cell proliferation and survival by transporting various proteins and non-coding RNAs (such as microRNAs and lncRNAs). In this study, miR-21 was highly enriched in exosomes derived from bone marrow mesenchymal stem cells (MSCs). Interestingly, exosomes collected from hydrogen peroxide (H2O2)-treated MSCs (H-Exo) contained higher levels of miR-21 than exosomes released from MSCs under normal conditions (N-Exo). The pre-treatment of C-kit+ cardiac stem cells (CSCs) with H-Exos resulted in significantly increased levels of miR-21 and phosphor-Akt (pAkt) and decreased levels of PTEN, which is a known target of miR-21. AnnexinV-FITC/PI analysis further demonstrated that the degree of oxidative stress-induced apoptosis was markedly lower in H-Exo-treated C-kit+ CSCs than that in N-Exo-treated cells. These protective effects could be blocked by both a miR-21 inhibitor and the PI3K/Akt inhibitor LY294002. Therefore, exosomal miR-21 derived from H2O2-treated MSCs could be transported to C-kit+ cardiac stem cells to functionally inhibit PTEN expression, thereby activating PI3K/AKT signaling and leading to protection against oxidative stress-triggered cell death. Thus, exosomes derived from MSCs could be used as a new therapeutic vehicle to facilitate C-kit+ CSC therapies in the ischemic myocardium.

show abstract

“…Overall, very few substrates have been identified for ERK8 homologs. The only known cellular substrate of HsERK8 to date is the RNA binding protein HuR, 28 which is encoded by the ELAVL1 gene. HuR binds to the 3′UTR of the PDC4 tumor suppressor to protect it from miRNA 21 mediated gene silencing.…”

Section: Discussionmentioning

confidence: 99%

Extracellular-signal regulated kinase 8 of Trypanosoma brucei uniquely phosphorylates its proliferating cell nuclear antigen homolog and reveals exploitable properties

2016

View full text Add to dashboard Cite

The Trypanosoma brucei subspecies T. brucei gambiense and T. brucei rhodesiense are vector-borne pathogens that cause sleeping sickness also known as Human African Trypanosomiasis (HAT), which is fatal if left untreated. The drugs that treat HAT are ineffective and cause toxic side effects. One strategy for identifying safer and more effective HAT drugs is to therapeutically exploit essential gene targets in T. brucei. Genes that make up a basic mitogen-activated protein kinase (MAPK) network are present in T. brucei. Tb927.10.5140 encodes an essential MAPK that is homologous to the human extracellular-signal regulated kinase 8 (HsERK8) which forms a tight complex with the replication factor proliferating cell nuclear antigen (PCNA) to stabilize intracellular PCNA levels. Here we demonstrate that (TbPCNA) is uniquely phos-phorylated on serine (S) and threonine (T) residues in T. brucei and that TbERK8 phosphorylates TbPCNA at each of these residues. The ability of an ERK8 homolog to phosphorylate a PCNA homolog is a novel biochemical property that is first demonstrated here in T. brucei and may be unique to this pathogen. We demonstrate that the potent HsERK8 inhibitor Ro318220, has an IC50 for TbERK8 that is several hundred times higher than its reported IC50 for HsERK8. This indicated that the active sites of TbERK8 and HsERK8 can be selectively inhibited, which provides a rational basis for discovering inhibitors that specifically target this essential parasite MAPK to kill the parasite.

show abstract

ERK8 is a novel HuR kinase that regulates tumour suppressor PDCD4 through a miR-21 dependent mechanism

Cited by 25 publications

References 41 publications

Potential Role of Exosomes in Mending a Broken Heart: Nanoshuttles Propelling Future Clinical Therapeutics Forward

Potential Role of Exosomes in Mending a Broken Heart: Nanoshuttles Propelling Future Clinical Therapeutics Forward

Bone marrow mesenchymal stem cell-derived exosomal miR-21 protects C-kit+ cardiac stem cells from oxidative injury through the PTEN/PI3K/Akt axis

Extracellular-signal regulated kinase 8 of Trypanosoma brucei uniquely phosphorylates its proliferating cell nuclear antigen homolog and reveals exploitable properties

Contact Info

Product

Resources

About