Molecular mechanisms that funnel RNA precursors into endogenous small-interfering RNA and microRNA biogenesis pathways in Drosophila

The enzyme Dicer is best known for its role as a riboendonuclease in the small RNA pathway. In this canonical role, Dicer is a critical regulator of the biogenesis of microRNA and small interfering RNA, as well as a growing number of additional small RNAs derived from various sources. Emerging evidence demonstrates that Dicer's endonuclease role extends beyond the generation of small RNAs; it is also involved in processing additional endogenous and exogenous substrates, and is becoming increasingly implicated in regulating a variety of other cellular processes, outside of its endonuclease function. This review will describe the canonical and newly identified functions of Dicer.

Download Full-text

Twist Modulates Human Trophoblastic Cell Invasion via Regulation of N-Cadherin

Endocrinology ◽

10.1210/en.2011-1488 ◽

2012 ◽

Vol 153 (2) ◽

pp. 925-936 ◽

Cited By ~ 26

Author(s):

York Hunt Ng ◽

Hua Zhu ◽

Peter C. K. Leung

Keyword(s):

Cell Invasion ◽

Small Interfering Rna ◽

Molecular Mechanisms ◽

Dependent Manner ◽

Trophoblastic Cell ◽

Protein Levels ◽

Bewo Cells ◽

Interfering Rna ◽

Tgf Β1

The invasion of extravillous cytotrophoblasts (EVT) into the underlying maternal tissues and vasculature is a key step in human placentation. The molecular mechanisms involved in the development of the invasive phenotype of EVT include many that were first discovered for their role in cancer cell metastasis. Previous studies have demonstrated that N-cadherin and its regulatory transcription factor Twist play important roles in the onset and progression of cancers, but their roles in human trophoblastic cell invasion is not clear. The goal of the study was to examine the role of Twist and N-cadherin in human trophoblastic cell invasion. Twist and N-cadherin mRNA and protein levels were determined by RT-PCR and Western blotting in human placental tissues, highly invasive EVT, and poorly invasive JEG-3 and BeWo cells. Whether IL-1β and TGF-β1 regulate Twist mRNA and protein levels in the EVT was also examined. A small interfering RNA strategy was employed to determine the role of Twist and N-cadherin in HTR-8/SVneo cell invasion. Matrigel assays were used to assess cell invasion. Twist and N-cadherin were highly expressed in EVT but were poorly expressed in JEG-3 and BeWo cells. IL-1β and TGF-β1 differentially regulated Twist expression in EVT in a time- and concentration-dependent manner. Small interfering RNA specific for Twist decreased N-cadherin and reduced invasion of HTR-8/SVneo cells. Similarly, a reduction in N-cadherin decreased the invasive capacity of HTR-8/SVneo cells. Twist is an upstream regulator of N-cadherin-mediated invasion of human trophoblastic cells.

Download Full-text

miR-487a performs oncogenic functions in osteosarcoma by targeting BTG2 mRNA

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa034 ◽

2020 ◽

Vol 52 (6) ◽

pp. 631-637

Author(s):

Zhiqian Gu ◽

Shaokun Wu ◽

Guoxing Xu ◽

Wei Wu ◽

Bo Mao ◽

...

Keyword(s):

Cell Growth ◽

Mirna Expression ◽

Small Interfering Rna ◽

Molecular Mechanisms ◽

Critical Role ◽

Clinical Samples ◽

Novel Target ◽

Induced Apoptosis ◽

Interfering Rna

Abstract Aberrant microRNA (miRNA) expression plays a critical role in osteosarcoma (OS) pathogenesis. In this study, we elucidated the involvement of miR-487a in OS and the underlying molecular mechanisms. We found that miR-487a was upregulated in OS clinical samples and cell lines. Knockdown of miR-487a suppressed OS cell growth and invasion and induced apoptosis; however, overexpression of miR-487a promoted OS cell growth and invasion. Accordingly, downregulation of miR-487a significantly suppressed tumor growth of OS xenografts in vivo. Furthermore, B-cell translocation gene 2 (BTG2) mRNA was found to be a novel target of miR-487a. Knockdown of BTG2 using small interfering RNA (siRNA) recapitulated the oncogenic effects of miR-487a, whereas BTG2 overexpression partially reversed these effects. Finally, miR-487a levels were found to be negatively correlated with BTG2 expression in OS clinical samples. Collectively, our data suggest that miR-487a is an oncogenic miRNA in OS and it lowers BTG2 expression.

Download Full-text

Protein disulfide isomerase increases in myocardial endothelial cells in mice exposed to chronic hypoxia: a stimulatory role in angiogenesis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00937.2008 ◽

2009 ◽

Vol 297 (3) ◽

pp. H1078-H1086 ◽

Cited By ~ 26

Author(s):

Fei Tian ◽

Xianghua Zhou ◽

Johannes Wikström ◽

Helen Karlsson ◽

Helén Sjöland ◽

...

Keyword(s):

Myocardial Infarction ◽

Endothelial Cells ◽

Protein Disulfide Isomerase ◽

Small Interfering Rna ◽

Molecular Mechanisms ◽

Chronic Hypoxia ◽

Cellular Migration ◽

Disulfide Isomerase ◽

Interfering Rna ◽

Protein Disulfide

Previous studies have shown that exposure to chronic hypoxia protects against myocardial infarction, but little is known about the cellular and molecular mechanisms involved. Here we observed that chronic hypoxia for 3 wk resulted in improved survival of mice (from 64% to 83%), reduced infarction size (from 45 ± 4% to 32 ± 4%, P < 0.05), increased cardiac ejection fraction (from 19 ± 4% to 35 ± 5%, P < 0.05), coronary flow velocity under adenosine-induced hyperemia (from 58 ± 2 to 75 ± 5 cm/s, P < 0.05), myocardial capillary density (from 3,772 ± 162 to 4,760 ± 197 capillaries/mm2, P < 0.01), and arteriolar density (from 8.04 ± 0.76 to 10.34 ± 0.69 arterioles/mm2, P < 0.05) 3 wk after myocardial infarction. With two-dimensional gel electrophoresis, we identified that protein disulfide isomerase (PDI) was highly upregulated in hypoxic myocardial capillary endothelial cells. The loss of PDI function in endothelial cells by small interfering RNA significantly increased the number of apoptotic cells (by 3.4-fold at hypoxia, P < 0.01) and reduced migration (by 52% at hypoxia, P < 0.001) and adhesion to collagen I (by 42% at hypoxia, P < 0.01). In addition, the specific inhibition of PDI by PDI small interfering RNA (by 46%, P < 0.01) and bacitracin (by 72%, P < 0.001) reduced the formation of tubular structures by endothelial cells. Our data indicate that chronic hypoxic exposure improves coronary blood flow and protects the myocardium against infarction. These beneficial effects may be partly explained by the increased endothelial expression of PDI, which protects cells against apoptosis and increases cellular migration, adhesion, and tubular formation. The increased PDI expression in endothelial cells may be a novel mechanism to protect the myocardium against myocardial ischemic diseases.

Download Full-text

HMGA1 Attenuates Doxorubicin-Induced Cardiomyocyte Pyroptosis By Inhibiting SOX9

10.21203/rs.3.rs-627801/v1 ◽

2021 ◽

Author(s):

Yaxiu Liu ◽

Yao Tang ◽

Hui Fu ◽

Shuang Fu ◽

Xinbin Zheng ◽

...

Keyword(s):

Small Interfering Rna ◽

Molecular Mechanisms ◽

Caspase 3 ◽

High Mobility ◽

Underlying Mechanism ◽

High Mobility Group ◽

Hmg Box ◽

Interfering Rna

Abstract Doxorubicin (DOX) is widely used as an anti-tumor drug with severe cardiotoxicity, encephalotoxicity, nephrotoxicity and so on, especially cardiotoxicity, which severely limit its application. Researchers have extensively studied the mechanisms of DOX-induced cardiotoxicity. However, the underlying mechanism of DOX-induced cardiotoxicity needs to be further evaluated. Studies reveal that High-mobility group AT-hook1 (HMGA1) and Sex-determining-region-Y (SRY)-related HMG box-containing protein 9 (SOX9) contribute to caspase-3-mediated apoptosis, but whether HMGA1 and SOX9 participate in caspase-3/gasdermin E (GSDME)-mediated pyroptosis remains unknown. This study was performed to investigate whether HMGA1 and SOX9 participate in DOX-induced cardiomyocyte pyroptosis induced by DOX in vitro, and to reveal the molecular mechanisms of HMGA1 and SOX9 in regulating DOX-induced cardiomyocyte pyroptosis via caspase/GSDME pathway. Results showed that the expression of HMGA1 is significantly up-regulated while SOX9 is down-regulated in HL-1 cells after DOX treatment. We found that both inhibition of HMGA1 by small interfering RNA (siRNA) and overexpression of SOX9 by transfection of SOX9 plasmid significantly promote cardiomyocyte pyroptosis induced by DOX. In addition, HMGA1 interacts with SOX9. Finally, our results show that silencing SOX9 reverses cardiomyocyte pyroptosis induced by silencing HMGA1 after DOX treatment.

Download Full-text

Stress Kinase Signaling Regulates Androgen Receptor Phosphorylation, Transcription, and Localization

Molecular Endocrinology ◽

10.1210/me.2005-0351 ◽

2006 ◽

Vol 20 (3) ◽

pp. 503-515 ◽

Cited By ~ 123

Author(s):

Daniel Gioeli ◽

Ben E. Black ◽

Vicki Gordon ◽

Adam Spencer ◽

Cristina T. Kesler ◽

...

Keyword(s):

Androgen Receptor ◽

Nuclear Export ◽

Small Interfering Rna ◽

Molecular Mechanisms ◽

Specific Antigen ◽

Mrna Levels ◽

Kinase Signaling ◽

Stress Kinase ◽

Interfering Rna ◽

Pharmacologic Inhibition

Abstract Activation of signal transduction kinase cascades is known to alter androgen receptor (AR) activity, but the molecular mechanisms are still poorly defined. Here we show that stress kinase signaling regulates Ser 650 phosphorylation and AR nuclear export. In LNCaP prostate cancer cells, activation of either MAPK kinase (MKK) 4:c-Jun N-terminal kinase (JNK) or MKK6:p38 signaling pathways increased Ser 650 phosphorylation, whereas pharmacologic inhibition of JNK or p38 signaling led to a reduction of AR Ser 650 phosphorylation. Both p38α and JNK1 phosphorylated Ser 650 in vitro. Small interfering RNA-mediated knockdown of either MKK4 or MKK6 increased endogenous prostate-specific antigen (PSA) transcript levels, and this increase was blocked by either bicalutamide or AR small interfering RNA. Stress kinase inhibition of PSA transcription is, therefore, dependent on the AR. Similar experiments involving either activation or inhibition of MAPK/ERK kinase:ERK signaling had little effect on Ser 650 phosphorylation or PSA mRNA levels. Ser 650 is proximal to the DNA binding domain that contains a nuclear export signal. Mutation of Ser 650 to alanine reduced nuclear export of the AR, whereas mutation of Ser 650 to the phosphomimetic amino acid aspartate restored AR nuclear export. Pharmacologic inhibition of stress kinase signaling reduced wild-type AR nuclear export equivalent to the S650A mutant without affecting nuclear export of the S650D mutant. Our data suggest that stress kinase signaling and nuclear export regulate AR transcriptional activity.

Download Full-text