Letrozole regulates actin cytoskeleton polymerization dynamics in a SRC-1 dependent manner in the hippocampus of mice

Zhao, Yangang; Yu, Yang; Zhang, Yuanyuan; He, Li; Qiu, Liang; Zhao, Jingming; Liu, Mengying; Zhang, Jiqiang

doi:10.1016/j.jsbmb.2016.11.013

Cited by 19 publications

(20 citation statements)

References 51 publications

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“…Rapid estrogenic signaling mediated through ERα (Sanchez et al, 2009 ) activates Src/Rho/Cdk5, WAVE1 pathway and a RhoA/ROCK-2/Moesin cascade, which cause the protrusion of dendritic spines (Polleux and Snider, 2010 ; Srivastava et al, 2013b ). It has been suggested that estradiol is a modulator of these processes (Srivastava et al, 2010 ; Sellers et al, 2015b ; Zhao et al, 2017 ). Other CDKs have been implicated in cell cycle regulation.…”

Section: Cytoarchitecture-specific Mechanism Involved In Sexual Diffementioning

confidence: 99%

Estradiol and the Development of the Cerebral Cortex: An Unexpected Role?

Denley¹,

Gatford²,

Sellers³

et al. 2018

Front. Neurosci.

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The cerebral cortex undergoes rapid folding in an “inside-outside” manner during embryonic development resulting in the establishment of six discrete cortical layers. This unique cytoarchitecture occurs via the coordinated processes of neurogenesis and cell migration. In addition, these processes are fine-tuned by a number of extracellular cues, which exert their effects by regulating intracellular signaling pathways. Interestingly, multiple brain regions have been shown to develop in a sexually dimorphic manner. In many cases, estrogens have been demonstrated to play an integral role in mediating these sexual dimorphisms in both males and females. Indeed, 17β-estradiol, the main biologically active estrogen, plays a critical organizational role during early brain development and has been shown to be pivotal in the sexually dimorphic development and regulation of the neural circuitry underlying sex-typical and socio-aggressive behaviors in males and females. However, whether and how estrogens, and 17β-estradiol in particular, regulate the development of the cerebral cortex is less well understood. In this review, we outline the evidence that estrogens are not only present but are engaged and regulate molecular machinery required for the fine-tuning of processes central to the cortex. We discuss how estrogens are thought to regulate the function of key molecular players and signaling pathways involved in corticogenesis, and where possible, highlight if these processes are sexually dimorphic. Collectively, we hope this review highlights the need to consider how estrogens may influence the development of brain regions directly involved in the sex-typical and socio-aggressive behaviors as well as development of sexually dimorphic regions such as the cerebral cortex.

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Section: Cytoarchitecture-specific Mechanism Involved In Sexual Diffementioning

confidence: 99%

Estradiol and the Development of the Cerebral Cortex: An Unexpected Role?

Denley¹,

Gatford²,

Sellers³

et al. 2018

Front. Neurosci.

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“…For the LET treatment, the dose employed (160 μg/kg BW) was based on our previous studies that showed hippocampal SRC-1 and actin polymerization were dose-dependently regulated by LET. 41 The mTORC2-specific activator A4 (HY-10425; Medchem Express, Shanghai, China) 37 was prepared with DMSO and intraperitoneally injected with a dose of 2.5 mg/kg body weight as previous reports. 37,38 Animals in the DMSO and/or sham groups received an injection of an equal amount of vehicle (60% DMSO + 40% sterile saline solution) as indicated in each experiment.…”

Section: The Selective Gpr30 Agonist G1 (10008933 Cayman Chemicalmentioning

confidence: 99%

“…37 After behavior test, protein of the hippocampus from three mice was extracted and the F-actin to G-actin ratio was determined by Western blot as previously described. 37,41 Briefly, the hippocampus was isolated and homogenized in cold lysis buffer…”

Section: F-actin/g-actin Ratio Measurementmentioning

confidence: 99%

“…The classic nuclear estrogen receptors ERα and ERβ have been implicated in the regulation of learning and memory, 13,15,47 and SRC-1 has been shown to be involved in the LET regulation of hippocampal PSD95 48 and actin polymerization. 41 Western blot and one-way for SRC-1). Further analysis indicated these proteins were downregulated by OVX compared with the sham animals (by 32%, 34%, and 33%, respectively; P < 0.01).…”

Section: Gpr30 Activation Reversed Ovx-induced Changes In Classic Nmentioning

confidence: 99%

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GPR30‐mediated estrogenic regulation of actin polymerization and spatial memory involves SRC‐1 and PI3K‐mTORC2 in the hippocampus of female mice

Zhang

Liu

et al. 2019

CNS Neurosci Ther

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Summary Aims The G‐protein‐coupled estrogen receptor GPR30 (also referred to as GPER) has been implicated in the estrogenic regulation of hippocampal plasticity and spatial memory; however, the molecular mechanisms are largely unclear. Methods In this study, we initially examined the levels of GPR30 in the hippocampus of postnatal, ovariectomy (OVX)‐ and letrozole (LET)‐treated female mice. Under G1, G15, and/or OVX treatment, the spatial memory, spine density, levels of ERα, ERβ, and SRC‐1, selected synaptic proteins, mTORC2 signals (Rictor and p‐AKT Ser473), and actin polymerization dynamics were subsequently evaluated. Furthermore, G1, G15, and/or E2 combined with SRC‐1 and/or PI3K inhibitors, actin cytoskeleton polymerization modulator JPK, and CytoD treatments were used to address the mechanisms that underlie GPR30 regulation in vitro. Finally, mTORC2 activator A‐443654 (A4) was used to explore the role of mTORC2 in GPR30 regulation of spatial memory. Results The results showed that high levels of GPR30 were detected in the adult hippocampus and the levels were downregulated by OVX and LET. OVX induced an impairment of spatial memory, and changes in other parameters previously described were reversed by G1 and mimicked by G15. Furthermore, the E2 effects on SRC‐1 and mTORC2 signals, synaptic proteins, and actin polymerization were inhibited by G15, whereas G1 effects on these parameters were inhibited by the blockade of SRC‐1 or PI3K; the levels of synaptic proteins were regulated by JPK and CytoD. Importantly, G15‐induced actin depolymerization and spatial memory impairment were rescued by mTORC2 activation with A4. Conclusions Taking together, these results demonstrated that decreased GPR30 induces actin depolymerization through SRC‐1 and PI3K/mTORC2 pathways and ultimately impairs learning and memory, indicating its potential role as a therapeutic target against hippocampus‐based, E2‐related memory impairments.

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“…[12][13][14] Nonetheless,s everal SRC-1i nhibitors have been developed to date. [15][16][17][18] Fori nstance, as mall molecule targeting both SRC-1 and SRC-3 recently reported by OMalley and co-workers exhibited potent in vitro and in vivo activities. [17] However,t hey lack the selectivity to SRC-1, and their mode of action remains unclear.…”

Section: Introductionmentioning

confidence: 96%

Targeted Degradation of Transcription Coactivator SRC‐1 through the N‐Degron Pathway

et al. 2020

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Aberrantly elevated steroid receptor coactivator‐1 (SRC‐1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC‐1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N‐degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC‐1 in cells through the N‐degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC‐1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC‐1 degrader can be an invaluable chemical tool in the studies of SRC‐1 functions. Moreover, our findings suggest PROTACs based on the N‐degron pathway as a widely useful strategy to degrade disease‐relevant proteins.

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Letrozole regulates actin cytoskeleton polymerization dynamics in a SRC-1 dependent manner in the hippocampus of mice

Cited by 19 publications

References 51 publications

Estradiol and the Development of the Cerebral Cortex: An Unexpected Role?

Estradiol and the Development of the Cerebral Cortex: An Unexpected Role?

GPR30‐mediated estrogenic regulation of actin polymerization and spatial memory involves SRC‐1 and PI3K‐mTORC2 in the hippocampus of female mice

Targeted Degradation of Transcription Coactivator SRC‐1 through the N‐Degron Pathway

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