Heat shock induces the nuclear accumulation of YAP1 via SRC.

Yes-associated protein 1 (YAP1), a co-transcription activator, shuttles between the cytoplasm and the nucleus. Phosphorylation by large tumor suppressor kinases (LATS1/2) is the major determinant of YAP1 subcellular localization. Unphosphorylated YAP1 interacts with transcription factors in the nucleus and regulates gene transcription, while phosphorylated YAP1 is trapped in the cytoplasm and is degraded. We found that when U2OS and HeLa cells are exposed to 42 °C, YAP1 enters the nucleus within 30 min and returns to the cytoplasm at 4 h. SRC and HSP90 are involved in nuclear accumulation and return to the cytoplasm, respectively. Upon heat shock, LATS2 forms aggregates including protein phosphatase 1 and is dephosphorylated and inactivated. SRC activation is necessary for the formation of aggregates, while HSP90 is required for their dissociation. YAP1 is involved in heat shock-induced NF-κB signaling. Mechanistically, YAP1 is implicated in strengthening the interaction between RELA and DPF3, a component of SWI/SNF chromatin remodeling complex, in response to heat shock. Thus, YAP1 plays a role as a thermosensor.

Comparison of CUMS at different pregnancy stages, maternal separation, and their effects on offspring in postpartum depression mouse models.

Due to the diversity of postpartum depression (PPD) patients and the complexity of associated pathophysiological changes, most current animal models cannot accurately simulate PPD-like symptoms. In this study, we established a reliable animal model for PPD by inducing chronic unpredictable mild stress (CUMS) at different stages (pre-pregnancy, pregnancy, or postnatal) in female mice, followed by maternal separation (MS) from day 2-21 after delivery. The results for female mice subjected to pre-pregnancy stress were not statistically significant due to a lower conception rate. However, female mice exposed to CUMS during either the gestational or postnatal stage, followed by MS, successfully exhibited PPD-like symptoms. The models were deemed effective based on observed behavioral abnormalities, impaired hippocampal neuron functioning, and reduced serum concentrations of neurotransmitters (5-HT, GABA, and NE). Additionally, mice that underwent gestational CUMS followed by MS displayed a more dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and more severe uterine inflammation. The study also investigated the impact of PPD on the behavior and neurodevelopment of adolescent offspring through behavioral tests, enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, and western blotting (WB). The results indicated that adolescent offspring of mothers with PPD exhibited behavioral and neurodevelopmental disorders, with male offspring being more susceptible than females. Female mice exposed to both CUMS and MS during the postnatal period had more severe adverse effects on their offspring compared to the other model groups.

Supercritical Fluid-extracted Citrus aurantium L. var. amara Engl. Essential Oil Nanoemulsion: Preparation, Characterization, and Its Sleep-promoting Effect.

To overcome the defects of Citrus aurantium L. var. amara Engl. essential oil (CAEO), such as high volatility and poor stability, supercritical fluid-extracted CAEO nanoemulsion (SFE-CAEO-NE) was prepared by the microemulsification method. Emulsifiers comprising Tween 80, polyoxyethylenated castor oil (EL-40), and 1,2-hexanediol, and an oil phase containing SFE-CAEO were used for microemulsification. We examined the physicochemical properties of SFE-CAEO-NE and steam distillation-extracted CAEO nanoemulsion (SDE-CAEO-NE), which were prepared using different concentrations of the emulsifiers. The mean particle size and zeta potential were 21.52 nm and -9.82 mV, respectively, for SFE-CAEO-NE, and 30.58 nm and -6.28 mV, respectively, for SDE-CAEO-NE, at an emulsifier concentration of 15% (w/w). SFE-CAEO-NE displayed better physicochemical properties compared with SDE-CAEO-NE. Moreover, its physicochemical properties were generally stable at different temperatures (-20-60℃), pH (3-8), and ionic strengths (0-400 mM). No obvious variations in particle size, zeta potential, and Ke were observed after storing this nanoemulsion for 30 days at 4℃, 25℃, and 40℃, suggesting that it had good stability. The sleep-promoting effect of SFE-CAEO-NE was evaluated using a mouse model of insomnia. The results of behavioral tests indicated that SFE-CAEO-NE ameliorated insomnia-like behavior. Moreover, SFE-CAEO- NE administration increased the serum concentrations of neurotransmitters such as 5-hydroxytryptamine and γ-aminobutyric acid, and decreased that of noradrenaline in mice. It also exerted a reparative effect on the function of damaged neurons. Overall, SFE-CAEO-NE displayed a good sleep-promoting effect.

Novel YAP1 Activator, Identified by Transcription-Based Functional Screen, Limits Multiple Myeloma Growth.

Yes-associated protein 1 (YAP1) interacts with numerous transcription factors, including TEA-domain family proteins (TEAD) and p73. YAP1 is negatively regulated by the tumor suppressor Hippo pathway. In human cancers, the deregulation of the Hippo pathway and YAP1 gene amplification lead to the activation of YAP1, which induces epithelial-mesenchymal transition (EMT) and drug resistance. YAP1 inhibitors are expected to be useful in cancer therapy. On the other hand, in certain cancers, YAP1 upregulates p73-dependent gene transcription and behaves as a tumor suppressor. Moreover, as YAP1 regulates self-renewal and differentiation of tissue stem cells and plays an important role in tissue homeostasis, YAP1 activators may contribute to the regenerative medicine. With this in our mind, we screened for YAP1 activators by using human retinal pigment epithelial ARPE-19 cells expressing the TEAD-responsive fluorescence reporter under the coexpression of YAP1. From an extensive chemical compound library (n = 18,606) 47 candidate YAP1 activators were identified. These compounds were characterized to determine whether this assay provides bona fide YAP1 activators. Importantly, one YAP1 activator was effective against the human multiple myeloma IM-9 cells and chronic myeloid leukemia K562 cells.Implications: YAP1 activation limits growth, induces apoptosis, and may be useful at suppressing hematological cancers. Mol Cancer Res; 16(2); 197-211. ©2017 AACR.

RASSF6; the Putative Tumor Suppressor of the RASSF Family.

Humans have 10 genes that belong to the Ras association (RA) domain family (RASSF). Among them, RASSF7 to RASSF10 have the RA domain in the N-terminal region and are called the N-RASSF proteins. In contradistinction to them, RASSF1 to RASSF6 are referred to as the C-RASSF proteins. The C-RASSF proteins have the RA domain in the middle region and the Salvador/RASSF/Hippo domain in the C-terminal region. RASSF6 additionally harbors the PSD-95/Discs large/ZO-1 (PDZ)-binding motif. Expression of RASSF6 is epigenetically suppressed in human cancers and is generally regarded as a tumor suppressor. RASSF6 induces caspase-dependent and -independent apoptosis. RASSF6 interacts with mammalian Ste20-like kinases (homologs of Drosophila Hippo) and cross-talks with the Hippo pathway. RASSF6 binds MDM2 and regulates p53 expression. The interactions with Ras and Modulator of apoptosis 1 (MOAP1) are also suggested by heterologous protein-protein interaction experiments. RASSF6 regulates apoptosis and cell cycle through these protein-protein interactions, and is implicated in the NF-κB and JNK signaling pathways. We summarize our current knowledge about RASSF6 and discuss what common and different properties RASSF6 and the other C-RASSF proteins have.