Therapeutic targeting of p90 ribosomal S6 kinase

The Serine/Threonine protein kinase family, p90 ribosomal S6 kinases (RSK) are downstream effectors of extracellular signal regulated kinase 1/2 (ERK1/2) and are activated in response to tyrosine kinase receptor or G-protein coupled receptor signaling. RSK contains two distinct kinase domains, an N-terminal kinase (NTKD) and a C-terminal kinase (CTKD). The sole function of the CTKD is to aid in the activation of the NTKD, which is responsible for substrate phosphorylation. RSK regulates various homeostatic processes including those involved in transcription, translation and ribosome biogenesis, proliferation and survival, cytoskeleton, nutrient sensing, excitation and inflammation. RSK also acts as a major negative regulator of ERK1/2 signaling. RSK is associated with numerous cancers and has been primarily studied in the context of transformation and metastasis. The development of specific RSK inhibitors as cancer therapeutics has lagged behind that of other members of the mitogen-activated protein kinase signaling pathway. Importantly, a pan-RSK inhibitor, PMD-026, is currently in phase I/1b clinical trials for metastatic breast cancer. However, there are four members of the RSK family, which have overlapping and distinct functions that can vary in a tissue specific manner. Thus, a problem for transitioning a RSK inhibitor to the clinic may be the necessity to develop isoform specific inhibitors, which will be challenging as the NTKDs are very similar to each other. CTKD inhibitors have limited use as therapeutics as they are not able to inhibit the activity of the NTKD but could be used in the development of proteolysis-targeting chimeras

A chromatin-bound kinase, ERK8, protects genomic integrity by inhibiting HDM2-mediated degradation of the DNA clamp PCNA

ERK8 prevents genome instability by blocking the association of the HDM2 E3 ubiquitin ligase with the genome-protecting protein PCNA

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

RSK2 and ERα comrades-in-arms in homeostasis and transformation

The physiological response to estrogen differs according to the developmental stage. We show, in the adult, estrogen-responsiveness is driven by ERK1/2 (extracellular signal-regulated kinase 1/2) whereas its downstream effector, RSK2 (p90 ribosomal S6 kinase 2), prevents continuous ERK1/2 activity through regulation of oxidative stress. Bioinformatic analysis revealed RSK2 association with breast cancer risk and oral contraceptives

Extracellular Signal-Regulated Kinase 7, a Regulator of Hormone-Dependent Estrogen Receptor Destruction

Estrogen receptor alpha (ERα) degradation is regulated by ubiquitination, but the signaling pathways that modulate ERα turnover are unknown. We found that extracellular signal-regulated kinase 7 (ERK7) preferentially enhances the destruction of ERα but not the related androgen receptor. Loss of ERK7 was correlated with breast cancer progression, and all ERα-positive breast tumors had decreased ERK7 expression compared to that found in normal breast tissue. In human breast cells, a dominant-negative ERK7 mutant decreased the rate of endogenous ERα degradation >4-fold in the presence of hormone and potentiated estrogen responsiveness. ERK7 targets the ERα ligand-binding domain for destruction by enhancing its ubiquitination. Thus, ERK7 is a novel regulator of estrogen responsiveness through its control of ERα turnover

Australian Aboriginal children have higher hospitalization rates for otitis media but lower surgical procedures than non-Aboriginal children: A record linkage population-based cohort study

Introduction Otitis media (OM) is one of the most common infectious diseases affecting children globally and the most common reason for antibiotic prescription and paediatric surgery. Australian Aboriginal children have higher rates of OM than non-Aboriginal children; however, there are no data comparing OM hospitalization rates between them at the population level. We report temporal trends for OM hospitalizations and in-hospital tympanostomy tube insertion (TTI) in a cohort of 469,589 Western Australian children born between 1996 and 2012. Materials and methods We used the International Classification of Diseases codes version 10 to identify hospitalizations for OM or TTI recorded as a surgical procedure. Using age-specific population denominators, we calculated hospitalization rates per 1,000 child-years by age, year and level of socio-economic deprivation. Results There were 534,674 hospitalizations among 221,588 children hospitalized at least once before age 15 years. Aboriginal children had higher hospitalization rates for OM than non-Aboriginal children (23.3/1,000 [95% Confidence Interval (CI) 22.8,24.0] vs 2.4/1,000 [95% CI 2.3,2.4] child-years) with no change in disparity over time. Conversely non-Aboriginal children had higher rates of TTI than Aboriginal children (13.5 [95% CI 13.2,13.8] vs 10.1 [95% CI 8.9,11.4]). Children from lower socio-economic backgrounds had higher OM hospitalization rates than those from higher socio-economic backgrounds, although for Aboriginal children hospitalization rates were not statistically different across all levels of socio-economic disadvantage. Hospitalizations for TTI among non-Aboriginal children were more common among those from higher socio-economic backgrounds. This was also true for Aboriginal children; however, the difference was not statistically significant. There was a decline in OM hospitalization rates between 1998 and 2005 and remained stable thereafter. Conclusion Aboriginal children and children from lower socio-economic backgrounds were over-represented with OM-related hospitalizations but had fewer TTIs. Despite a decrease in OM and TTI hospitalization rates during the first half of the study for all groups, the disparity between Aboriginal and non-Aboriginal children and between those of differing socioeconomic deprivation remained.This study was funded through a National Health and Medical Research Council (NHMRC;www.nhmrc.gov.au) Project Grant (APP1045668). CCB is funded by National Health and Medical Research Council Fellowship (1111596) and HCM is funded by National Health and Medical Research Council Fellowship (1034254)

ERα-Mediated Nuclear Sequestration of RSK2 Is Required for ER +

Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to antiestrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of estrogen receptor-positive (ER+) breast cancer, we report that ER alpha sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ER alpha through its N terminus to activate a proneoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ER alpha status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high-grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Antiestrogens disrupted the interaction between RSK2 and ER alpha, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ER alpha-mediated transcriptional programs, tumorigenesis, and divergent patient responses to antiestrogen therapies. Significance: Nuclear accumulation of active RSK drives a protumorigenic transcriptional programand renders ER+ breast cancer susceptible to endocrine-based therapies. (C) 2018 AACR

Indicators for continuous quality improvement for otitis media in primary health care for Aboriginal and Torres Strait Islander children

Otitis media is a common, generally self-limiting childhood illness that can progress to severe disease and have lifelong sequelae, including hearing loss and developmental delays. Severe disease is disproportionately prevalent among Aboriginal and Torres Strait Islander children. Primary health care is at the frontline of appropriate prevention and treatment. Continuous quality improvement in the prevention and management of important causes of morbidity in client populations is accepted best practice in primary health care and now a requirement of Australian Government funding to services providing care for Aboriginal and Torres Strait Islander children. To date, there have been no indicators for continuous quality improvement in the prevention and management of otitis media and its sequelae in primary health care. Through an expert group consensus process, seven evidence-based indicators, potentially extractable from electronic health records, have been developed. The development process and indicators are describe

Stereoselective Synthesis and Evaluation of C6″-Substituted 5a‑Carbasugar Analogues of SL0101 as Inhibitors of RSK1/2

A convergent synthesis of 5a-carbasugar analogues of the <i>n</i>-Pr-variant of SL0101 is described. The analogues were synthesized in an effort to find compounds with potent <i>in vivo</i> efficacy in the inhibition of p90 ribosomal s6 kinase (RSK1/2). The synthesis derived the desired <i>C</i>-4 L-rhamnose stereochemistry from quinic acid and used a highly selective cuprate addition, NaBH₄ reduction, Mitsunobu inversion, and alkene dihydroxylation to install the remaining stereochemistry. A Pd-catalyzed cyclitolization stereoselectively installed the aglycon at the anomeric position. The analogues were evaluated as RSK1/2 inhibitors and found to have 3- to 6-fold improved activity