Although the short isoform of ErbB3-binding protein 1 (Ebp1), p42 has been considered to be a potent tumor suppressor in a number of human cancers, whether p42 suppresses tumorigenesis of lung cancer cells has never been clarified. In the current study we investigated the tumor suppressor role of p42 in non-small cell lung cancer cells. Our data suggest that the expression level of p42 is inversely correlated with the cancerous properties of NSCLC cells and that ectopic expression of p42 is sufficient to inhibit cell proliferation, anchorage-independent growth, and invasion as well as tumor growth in vivo. Interestingly, p42 suppresses Akt activation and overexpression of a constitutively active form of Akt restores the tumorigenic activity of A549 cells that is ablated by exogenous p42 expression. Thus, we propose that p42 Ebp1 functions as a potent tumor suppressor of NSCLC through interruption of Akt signaling. [BMB Reports 2015; 48(3): 159-165]

/pdf/p42-ebp1-functions-as-a-tumor-suppressor-in-non-small-cell-45i0t5j80p.pdf

P42 Ebp1 functions as a tumor suppressor in non-small cell lung cancer.

Introduction: Based on its role as a mitotic regulatory kinase, overexpressed and associated with aneuploidy in cancer, small-molecule inhibitors have been developed for Aurora-A (AURKA) kinase. In preclinical and clinical assessments, these agents have shown efficacy in inducing stable disease or therapeutic response. In optimizing the use of Aurora-A inhibitors, it is critical to have robust capacity to measure the kinase activity of Aurora-A in tumors.Areas covered: We provide an overview of molecular mechanisms of mitotic and non-mitotic activation of Aurora-A kinase, and interaction of Aurora-A with its regulatory partners. Typically, Aurora-A activity is measured by use of phospho-antibodies targeting an autophosphorylated T288 epitope. However, recent studies have identified alternative means of Aurora-A activation control, including allosteric regulation by partners, phosphorylation on alternative activating residues (S51, S98), dephosphorylation on inhibitory sites (S342) and T288 phosphorylation...

/pdf/issues-in-interpreting-the-in-vivo-activity-of-aurora-a-33kok6gsvy.pdf

Issues in interpreting the in vivo activity of Aurora-A

The epidermis, outermost layer of the skin, is constantly renewing itself through proliferative and differentiation processes. These processes are vital to maintain proper epidermal integrity during skin development and homeostasis and for preventing skin diseases and cancers. The biological mechanisms that permit this balancing act are vast, where individual pathway regulators are known, but the exact regulatory control and cross-talk between simultaneously turning one biological pathway on and an opposing one off remain elusive. This review explores the diverse roles the scaffolding protein AJUBA plays during epidermal homeostasis and cancer. Initially identified for its role in promoting meiotic progression in oocytes through Grb2 and MAP kinase activity, AJUBA also maintains cytoskeletal tension permitting epidermal tissue development and responds to retinoic acid committing cells to initiate development of surface epidermal layer. AJUBA regulates proliferation of skin stem cells through Hippo and Wnt signalling and encourages mitotic commitment through Aurora-A, Aurora-B and CDK1. In addition, AJUBA also induces epidermal differentiation to maintain appropriate epidermal thickness and barrier function by activating Notch signalling and stabilizing catenins and actin during cellular remodelling. AJUBA also plays an imperative context-dependent tumor-promoting and tumor-suppressive role within epithelial cancers. AJUBA's abundant roles within the epidermis signify its importance as a molecular switchboard, vetting multiple signalling pathways to control epidermal biology.

AJUBA: A regulator of epidermal homeostasis and cancer.

Aurora-A is a serine/threonine kinase, which is overexpressed in multiple human cancers and plays a key role in tumorigenesis and tumor development. In this study, we found that the receptor of activated C-kinase1 (RACK1), an important regulator of biological functions, interacted with Aurora-A and co-localized with Aurora-A at centrosomes. Moreover, RACK1 induces the auto-phosphorylation of Aurora-A in vitro and in vivo. Depletion of RACK1 impaired the activation of Aurora-A in late G2 phase, then inhibited the mitotic entry and leaded to multi-polarity, severe chromosome alignment defects, or centrosome amplification. Taken together, these results suggest that RACK1 is a new partner of Aurora-A and play a critical role in the regulation of the Aurora-A activity during mitosis, which may provide a basis for future anticancer studies targeting Aurora-A.

https://www.tandfonline.com/doi/pdf/10.1080/15384101.2019.1642065

RACK1 affects the progress of G2/M by regulating Aurora-A.

Esophageal squamous cell carcinoma (ESCC) is generally known to be a highly fatal cancer, and thus novel molecular targets are needed to improve its diagnosis and treatment. AJUBA has been shown to regulate cell cycle, adhesion, proliferation, apoptosis, and migration in many malignant tumors. However, the clinical significance of AJUBA in ESCC tumor metastasis remains unclear. In this study, we explored the role of AJUBA, Yes-associated protein 1 (YAP1), and matrix metalloproteinase 14 (MMP14) in the clinical presentation and survival of ESCC. Immunohistochemical staining showed higher expression of these proteins in cancer tissues than in paired adjacent tissues, and this upregulation was differently related to lymph node metastasis and TNM stage. AJUBA expression was positively correlated with that of YAP1. High expression of MMP14 was associated with reduced survival. In general, our findings reveal that AJUBA, YAP1, and MMP14 might function as oncoproteins and contribute to novel targeted therapy in ESCC.

Clinical significance of AJUBA, YAP1, and MMP14 expression in esophageal squamous cell carcinoma.

Aurora-A is a centrosome-localized serine/threonine kinase that is overexpressed in multiple human cancers. We previously reported an intramolecular inhibitory regulation of Aurora-A between its N-terminal regulatory domain (Nt, amino acids [aa] 1-128) and the C-terminal catalytic domain (Cd, aa 129-403). Here, we demonstrate that although both Aurora-A mutants (AurA-K250G and AurA-D294G/Y295G) lacked interactions between the Nt and Cd, they also failed to interact with Ajuba, an essential activator of Aurora-A, leading to loss of kinase activity. Additionally, overexpression of either of the mutants resulted in centrosome amplification and mitotic spindle formation defects. Both mutants were also able to cause G2/M arrest and apoptosis. These results indicate that both K250 and D294/Y295 are critical for direct interaction between Aurora-A and Ajuba and the function of the Aurora-A complex in cell cycle progression. [BMB Reports 2014; 47(11): 631-636]

Aurora-A kinase-inactive mutants disrupt the interaction with Ajuba and cause defects in mitotic spindle formation and G2/M phase arrest in HeLa cells.

Di-(2-ethylhexyl) phthalate (DEHP) is among the most widely used plasticizers in plastic production, which has been detected in various environments. However, DEHP safety remains poorly known. Using zebrafish models, the effects of DEHP on the angiogenesis and hematopoiesis, and the underlying mechanism, were studied. Transgenic zebrafish embryos with specific fluorescence of vascular endothelial cells, myeloid cells, or hematopoietic stem cells were exposed to 0, 100, 150, 200, or 250 nM of DEHP for 22, 46 or 70 h, followed by fluorescence observation, endogenous alkaline phosphatase activity measurement, erythrocyte staining, and gene expression analysis by quantitative PCR and whole mount in situ hybridization. High DEHP concentrations decreased the sprouting rate, average diameter, and length, and the expansion area of the vessels lowered the EAP activity and suppressed the vascular endothelial growth factor (vegf) and hematopoietic marker genes, including c-myb, hbae1, hbbe1, and lyz expressions. DEHP treatment also decreased the number of hematopoietic stem cells, erythrocytes, and myeloid cells at 24 and 72 hpf. These DEHP-induced angiogenetic and hematopoietic defects might be alleviated by vegf overexpression. Our results reveal a plausible mechanistic link between DEHP exposure-induced embryonic angiogenetic defect and hematopoietic impairment. 

Di-(2-ethylhexyl) phthalate impairs angiogenesis and hematopoiesis via suppressing VEGF signaling in zebrafish.

Background: The mechanism of a water-soluble extract of safflower on chronic alcoholic liver injury is still unclear. Objective: To study the mechanism of water extract of safflower on chronic alcoholic liver injury. Materials and Methods: The rats were separated in a random manner into five cohorts, namely, the normal control group (NC), alcoholic fatty liver disease model (ALD), ALD rat model treated with the water-soluble extract of safflower (30 g/kg), ALD rat model treated with the water-soluble extraction of safflower (40 g/kg), and ALD rat model with the water-soluble extract of safflower (50 g/kg). Rats in each group were anaesthetized with 2% isoflurane and euthanized by cervical dislocation after 1, 7, 14, 21, and 28 days treatment. Proteomic analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG analysis), immunohistochemistry (IHC), and western blot were employed for comparing the variations across model cohort and control cohort at the tissue level, protein level, and molecular level, respectively, and for probing potential prophylactic role/mechanisms for safflower extract on alcoholic liver injury. Results: KEGG analysis found that the differentially expressed genes in the alcoholic liver injury model were closely associated with alcoholism, inflammation, and serotonergic synapses. Furthermore, with the administration of water-soluble extract of safflower, these hepatic function indices and liver steatosis lesions were alleviated in both time and dose-dependent manners. Importantly, IHC analysis discovered that proteins disulfide isomerase A3 (PDIA3) and Trk-fused gene (TFG) were highly increased in the liver of the rats. Furthermore, the water-soluble extract of safflower alleviated liver oxidative injury and lipid peroxidation, via the upregulation of proteins such as 26S proteasome non-ATPase regulatory subunit 2 (PSMD2), cytochrome P450 2C6 (CYP2C6V1), and cytochrome P450 2C11 (CYP2C11), anddownregulation of arachidonate 12-lipoxygenase and 12S-type (ALOX12) protein expression. Conclusion: The water-soluble extract of safflower exhibited potential protective effects against lipid peroxidation and ethanol-driven oxidative damage within the liver via the upregulation of expression of proteins PSMD2, CYP2C6V1, and CYP2C11and downregulation of the expression of ALOX12, PDIA3, and TFG proteins.

Water-Soluble Extract of Safflower Relieved Long-Term Alcoholic Hepatic Damage through Mitigating Oxidative Stress Within Rat Model

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Aurora-A kinase-inactive mutants disrupt the interaction with Ajuba and cause defects in mitotic spindle formation and G2/M phase arrest in HeLa cells.

Di-(2-ethylhexyl) phthalate impairs angiogenesis and hematopoiesis via suppressing VEGF signaling in zebrafish.

Water-Soluble Extract of Safflower Relieved Long-Term Alcoholic Hepatic Damage through Mitigating Oxidative Stress Within Rat Model