scholarly journals Stxbp4 Regulates ΔNp63 Stability by Suppression of RACK1-Dependent Degradation

2009 ◽  
Vol 29 (14) ◽  
pp. 3953-3963 ◽  
Author(s):  
Yingchun Li ◽  
Melissa J. Peart ◽  
Carol Prives
Keyword(s):  
Squamous Cell Carcinoma ◽  
Normal Growth ◽  
Genotoxic Stress ◽  
Growth Conditions ◽  
Carcinoma Cells ◽  
Scaffold Proteins ◽  
Proliferating Cells ◽  
Protein Levels ◽  
Response To Stress

ABSTRACT p63, a member of the p53 tumor suppressor family, is essential for the development of epidermis as well as other stratified epithelia. Collective evidence indicates that ΔNp63 proteins, the N-terminally deleted versions of p63, are essential for the proliferation and survival of stratified epithelial cells and squamous cell carcinoma cells. But in response to DNA damage, ΔNp63 proteins are quickly downregulated in part through protein degradation. To elucidate the mechanisms by which ΔNp63 proteins are maintained at relatively high levels in proliferating cells but destabilized in response to stress, we sought to identify p63 interactive proteins that regulate p63 stability. We found that Stxbp4 and RACK1, two scaffold proteins, play central roles in balancing ΔNp63 protein levels. While Stxbp4 functions to stabilize ΔNp63 proteins, RACK1 targets ΔNp63 for degradation. Under normal growth conditions, Stxbp4 is indispensable for maintaining high basal levels of ΔNp63 and preventing RACK1-mediated p63 degradation. Upon genotoxic stress, however, Stxbp4 itself is downregulated, correlating with ΔNp63 destabilization mediated in part by RACK1. Taken together, we have delineated key mechanisms that regulate ΔNp63 protein stability in vivo.

scholarly journals Original Research: miR-194 inhibits proliferation and invasion and promotes apoptosis by targeting KDM5B in esophageal squamous cell carcinoma cells

2016 ◽  
Vol 242 (1) ◽  
pp. 45-52 ◽  
Author(s):  
Guanghui Cui ◽  
Donglei Liu ◽  
Weihao Li ◽  
Yuhang Li ◽  
Youguang Liang ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Target Prediction ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Original Research ◽  
Proliferation And Invasion

Increasing evidence suggests that miR-194 is down-regulated in esophageal squamous cell carcinoma tumor tissue. However, the role and underlying mechanism of miR-194 in esophageal squamous cell carcinoma have not been well defined. We used DIANA, TargetScan and miRanda to perform target prediction analysis and found KDM5B is a potential target of miR-194. Based on these findings, we speculated that miR-194 might play a role in esophageal squamous cell carcinoma development and progression by regulation the expression of KDM5B. We detected the expression of miR-194 and KDM5B by quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot assays, respectively, and found down-regulation of miR-194 and up-regulation of KDM5B existed in esophageal squamous cell carcinoma cell lines. By detecting proliferation, invasion and apoptosis of TE6 and TE14 cells transfected with miR-194 mimics or mimic control, miR-194 was found to inhibit proliferation and invasion and promote apoptosis of esophageal squamous cell carcinoma cells. miR-194 was further verified to regulate proliferation, apoptosis and invasion of esophageal squamous cell carcinoma cells by directly targeting KDM5B. Furthermore, animal studies were performed and showed that overexpression of miR-194 inhibited the growth of esophageal squamous cell carcinoma tumors in vivo. These results confirmed our speculation that miR-194 targets KDM5B to inhibit esophageal squamous cell carcinoma development and progression. These findings offer new clues for esophageal squamous cell carcinoma development and progression and novel potential therapeutic targets for esophageal squamous cell carcinoma.

scholarly journals Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiaofeng Qi ◽  
Wengguang Xu ◽  
Junqi Xie ◽  
Yufeng Wang ◽  
Shengwei Han ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Carcinoma Cells ◽  
Oral Cancers ◽  
Underlying Mechanisms

Abstract Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms. Encouragingly, we found that metformin synergistically enhanced cisplatin cytotoxicity and reversed the chemoresistance to certain extent. This mechanism could likely be related with inhibition of the NF-κB/HIF-1α signal axis and lead to the downregulation of hypoxia-regulated genes products. Therefore, metformin could serve as a chemosensitiser for cisplatin-based regimens for OSCC, thereby providing a theoretical basis for future use in the treatment of oral cancers.

Apatinib inhibits tumor progression and promotes antitumor efficacy of cytotoxic drugs in esophageal squamous cell carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15554-e15554
Author(s):  
Yanyan Chi ◽  
Feng Wang ◽  
Xiangrui Meng ◽  
Zhengzheng Shan ◽  
Yan Sun ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Cancer ◽  
Cell Growth ◽  
Western Blot ◽  
Cell Lines ◽  
Cytotoxic Drugs ◽  
Migration And Invasion ◽  
Protein Levels ◽  
Bax Protein

e15554 Background: Apatinib, a highly selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), inhibits the angiogenesis of tumors. The function and mechanism of Apatinib in esophageal squamous cell carcinoma (ESCC) remains unknown. Methods: The expression of VEGFR-2 in ESCC cell lines (KYSE450, EC1, KYSE410, KYSE70) were detected by western blot. KYSE450 and EC1 cell lines were treated with Apatinib, or combined with cytotoxic drugs: paclitaxel (TAX), 5-fluorouracil (5-FU) or cisplatin (DDP) respectively. Cell proliferation was then measured using CCK-8 assay; cell apoptosis was analyzed by flow cytometry; cell migration and invasion were evaluated by wound healing and transwell assays. The expression of VEGFR-2, Bcl2, MMP-2/MMP-9, p-Akt and p-mTOR in KYSE450 and EC1 cell lines were determined by western blot. Esophageal cancer xenografts model was established and used to evaluate the antitumor effects of combination of Apatinib and cytotoxic drugs in vivo. Immunohistochemistry was used to detect the expression of Ki67, VEGFR-2 and CD31 in tumor tissues of esophageal cancer xenografts model. Results: We found that Apatinib efficiently inhibited cell growth, metastasis and activity of the Akt/mTOR pathway in ESCC cells. Western blot analysis showed that Apatinib significantly increased Bax protein levels, decreased VEGFR-2, Bcl2, MMP-2/MMP-9, p-Akt and p-mTOR protein levels in ESCC cells. Moreover, Apatinib enhanced chemosensitivity of cytotoxic drugs TAX, 5-FU and DDP by upregulating expression of Bax protein, and downregulating expression of VEGFR-2, Bcl2, MMP-2/MMP-9 protein in vitro. Compared with single agent groups, the combination of Apatinib with each chemotherapeutic drug significantly repressed tumor growth and angiogenesis through blocking the expression of Ki67, VEGFR-2 and CD31 in vivo. Conclusions: Taken together, Apatinib suppressed cell growth, migration and invasion, and promoted antitumor effect of chemotherapeutic agents in ESCC.

scholarly journals Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells' Sensitivity to Cisplatin and Radiation In Vivo and In Vitro

2011 ◽  
Vol 17 (7) ◽  
pp. 1815-1827 ◽  
Author(s):  
Daisuke Sano ◽  
Fumihiko Matsumoto ◽  
David R. Valdecanas ◽  
Mei Zhao ◽  
David P. Molkentine ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Carcinoma Cells ◽  
Neck Squamous Cell Carcinoma

scholarly journals Filamentation in Candida albicans is modulated by adaptive translation of farnesol signalling genes

2021 ◽  
Author(s):  
Carla Oliveira ◽  
Ana Rita Guimarães ◽  
Inês Correia ◽  
Inês Sousa ◽  
Ana Poim ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Phenotypic Diversity ◽  
Critical Role ◽  
Normal Growth ◽  
Morphological Diversity ◽  
Growth Conditions ◽  
Response To Stress ◽  
Variable Morphology

AbstractThe complex biology of the human pathogen Candida albicans is reflected in its remarkable ability to proliferate in numerous body sites, adapt to drastic changes in the environment, form various types of colonies and grow in yeast, pseudo-hyphal and hyphal forms. Much has been learnt in recent years about the relevance of this phenotypic plasticity, but the mechanisms that support it are still not fully understood. We have demonstrated that atypical translation of the CUG codon is a source of unexpected morphological diversity. The CUG codon is translated as both leucine (Leu) (~3%) and serine (Ser) (~97%) in normal growth conditions, but Ser/Leu levels change in response to stress. Remarkably, recombinant C. albicans strains incorporating between 20% and 99% of Leu at CUG sites display a diverse array of phenotypes and produce colonies of variable morphology containing a mixture of yeast, pseudohyphal and hyphal cells. In this work we investigate the role of the CUG codon in the yeast-hypha transition. Our data show that increasing incorporation levels of Leu at CUG sites trigger hyphal initiation under non-inducing conditions by reducing farnesol production, and increasing the degradation of the Nrg1 hyphal repressor. We propose that dual CUG Ser/Leu translation triggers filamentation via the Nrg1 pathway.ImportanceThe unique translation of the CUG codon as both Ser (~97%) and Leu (~3%) plays a key role in the production of high genomic and phenotypic diversity in C. albicans. The molecular mechanisms that support such diversity are poorly understood. Here, we show that increased Leu incorporation at CUG sites induce hyphae formation in media where C. albicans normally grows in the yeast form. The data show that increasing Leu at CUG sites triggers the degradation of the hyphal repressor Nrg1, allowing for full expression of hyphal genes. Since filamentation is important for invasion of host tissues, this work shows how the atypical translation of a single codon may play a critical role in the virulence of all fungi of the CTG clade.

scholarly journals Differential expression of duplicated ribosomal protein genes modifies ribosome composition in response to stress

2019 ◽  
Vol 48 (4) ◽  
pp. 1954-1968 ◽  
Author(s):  
Mustafa Malik Ghulam ◽  
Mathieu Catala ◽  
Sherif Abou Elela
Keyword(s):  
Ribosomal Protein ◽  
Rna Polymerase Ii ◽  
Ribosomal Proteins ◽  
Normal Growth ◽  
Growth Conditions ◽  
Duplicated Genes ◽  
Ribosomal Protein Genes ◽  
Expression Ratio ◽  
Gene Copies ◽  
Response To Stress

Abstract In Saccharomyces cerevisiae, most ribosomal proteins are synthesized from duplicated genes, increasing the potential for ribosome heterogeneity. However, the contribution of these duplicated genes to ribosome production and the mechanism determining their relative expression remain unclear. Here we demonstrate that in most cases, one of the two gene copies generate the bulk of the active ribosomes under normal growth conditions, while the other copy is favored only under stress. To understand the origin of these differences in paralog expression and their contribution to ribosome heterogeneity we used RNA polymerase II ChIP-Seq, RNA-seq, polyribosome association and peptide-based mass-spectrometry to compare their transcription potential, splicing, mRNA abundance, translation potential, protein abundance and incorporation into ribosomes. In normal conditions a post-transcriptional expression hierarchy of the duplicated ribosomal protein genes is the product of the efficient splicing, high stability and efficient translation of the major paralog mRNA. Exposure of the cell to stress modifies the expression ratio of the paralogs by repressing the expression of the major paralog and thus increasing the number of ribosomes carrying the minor paralog. Together the data indicate that duplicated ribosomal protein genes underlie a modular network permitting the modification of ribosome composition in response to changing growth conditions.

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