scholarly journals Rapid degradation of ABCA1 protein following cAMP withdrawal and treatment with PKA inhibitor suggests ABCA1 is a short-lived protein primarily regulated at the transcriptional level

2020 ◽  
Vol 19 (1) ◽  
pp. 363-371
Author(s):  
Neelam Srivastava ◽  
Angelo B. Cefalu ◽  
Maurizio Averna ◽  
Rai Ajit K. Srivastava
Keyword(s):  
Transcriptional Level ◽  
Rapid Degradation ◽  
Abca1 Protein

Abstract 636: The Nuclear Receptor FXR Uncouples the Actions of Srebp2 and MiR-33

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Elizabeth Vallim ◽  
Hannah Ahn ◽  
Thomas Vallim
Keyword(s):  
Nuclear Receptor ◽  
Proteolytic Processing ◽  
Fine Tuning ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
Microrna Regulation ◽  
Protein Levels ◽  
New Findings ◽  
Direct Target Gene ◽  
Abca1 Protein

The role of microRNAs in fine-tuning gene expression has now been well established, but the mechanisms for microRNA regulation at the transcriptional level remain understudied. The physiologic context in which microRNAs are acting is likely linked to the function of these same microRNAs and how they are regulated. Here we identify miR-33 as a direct target gene of the bile acid nuclear receptor FXR. We show that pharmacologic FXR activation induces miR-33 in wild-type, but not FXR knockout mice. MiR-33 is located in the Srebp2 locus, and we show that FXR activation also induces the expression of Srebp2 mRNA. Using ChIP-Seq, we identify at least one functional FXRE in an intronic region of Srebp2, demonstrating that miR-33 and Srebp2 are both direct FXR targets. Although FXR activation increases Srebp2 mRNA levels, we also demonstrate that FXR in fact decreases Srebp2 proteolytic processing, which determines its transcriptional activity. This decreased activity is a result of the FXR dependent induction of the integral ER membrane protein Insig2, which is itself also a direct FXR target. Together these results identify a molecular mechanism for the transcriptional regulation of Srebp2 and miR-33, as well as the mechanism for the decreased activity of Srebp2 processing in the ER by FXR. The best characterized target of miR-33 is ABCA1. We have previously demonstrated that FXR activation decreases ABCA1 protein levels via the induction of miR-144, a microRNA that also targets ABCA1. Our new findings suggest that FXR induces two independent microRNAs that function together to repress ABCA1 and reduce HDL levels.

Endotoxin-Induced Tissue Factor in Human Monocytes is Dependent upon Protein Kinase C Activation

1993 ◽  
Vol 70 (05) ◽  
pp. 800-806 ◽  
Author(s):  
C Ternisien ◽  
M Ramani ◽  
V Ollivier ◽  
F Khechai ◽  
T Vu ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tissue Factor ◽  
Factor Ix ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Human Monocytes ◽  
Kinase C ◽  
Pkc Activation

SummaryTissue factor (TF) is a transmembrane receptor which, in association with factors VII and Vila, activates factor IX and X, thereby activating the coagulation protease cascades. In response to bacterial lipopolysaccharide (LPS) monocytes transcribe, synthesize and express TF on their surface. We investigated whether LPS-induced TF in human monocytes is mediated by protein kinase C (PKC) activation. The PKC agonists phorbol 12- myristate 13-acetate (PMA) and phorbol 12, 13 dibutyrate (PdBu) were both potent inducers of TF in human monocytes, whereas 4 alpha-12, 13 didecanoate (4 a-Pdd) had no such effect. Both LPS- and PMA-induced TF activity were inhibited, in a concentration dependent manner, by three different PKC inhibitors: H7, staurosporine and calphostin C. TF antigen determination confirmed that LPS-induced cell-surface TF protein levels decreased in parallel to TF functional activity under staurosporine treatment. Moreover, Northern blot analysis of total RNA from LPS- or PMA-stimulated monocytes showed a concentration-dependent decrease in TF mRNA levels in response to H7 and staurosporine. The decay rate of LPS-induced TF mRNA evaluated after the arrest of transcription by actinomycin D was not affected by the addition of staurosporine, suggesting that its inhibitory effect occurred at a transcriptional level. We conclude that LPS-induced production of TF and its mRNA by human monocytes are dependent on PKC activation.

CARP Plays a Key Role in Cellular Growth Under Hypertrophic Stimuli in Neonatal Rat Ventricular Myocytes

2013 ◽  
Vol 9 ◽  
Author(s):  
Tara A Shrout
Keyword(s):  
Gene Expression ◽  
Ventricular Myocytes ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Transcriptional Level ◽  
Dual Nature ◽  
Hypertrophic Growth ◽  
Rat Ventricular Myocytes ◽  
Neonatal Rat Ventricular Myocytes ◽  
Over Time

Cardiac hypertrophy is a growth process that occurs in response to stress stimuli or injury, and leads to the induction of several pathways to alter gene expression. Under hypertrophic stimuli, sarcomeric structure is disrupted, both as a consequence of gene expression and local changes in sarcomeric proteins. Cardiac-restricted ankyrin repeat protein (CARP) is one such protein that function both in cardiac sarcomeres and at the transcriptional level. We postulate that due to this dual nature, CARP plays a key role in maintaining the cardiac sarcomere. GATA4 is another protein detected in cardiomyocytes as important in hypertrophy, as it is activated by hypertrophic stimuli, and directly binds to DNA to alter gene expression. Results of GATA4 activation over time were inconclusive; however, the role of CARP in mediating hypertrophic growth in cardiomyocytes was clearly demonstrated. In this study, Neonatal Rat Ventricular Myocytes were used as a model to detect changes over time in CARP and GATA4 under hypertrophic stimulation by phenylephrine and high serum media. Results were detected by analysis of immunoblotting. The specific role that CARP plays in mediating cellular growth under hypertrophic stimuli was studied through immunofluorescence, which demonstrated that cardiomyocyte growth with hypertrophic stimulation was significantly blunted when NRVMs were co-treated with CARP siRNA. These data suggest that CARP plays an important role in the hypertrophic response in cardiomyocytes.

Regulation of gene expression during spermatogenesis at transcriptional level

2011 ◽  
Vol 33 (12) ◽  
pp. 1300-1307
Author(s):  
Xiu-Jun ZHANG ◽  
Mei-Ling LIU ◽  
Meng-Chun JIA
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Transcriptional Level

UBE2L6 is Involved in Cisplatin Resistance by Regulating the Transcription of ABCB6

2020 ◽  
Vol 20 (12) ◽  
pp. 1487-1496 ◽  
Author(s):  
Midori Murakami ◽  
Hiroto Izumi ◽  
Tomoko Kurita ◽  
Chiho Koi ◽  
Yasuo Morimoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Promoter Activity ◽  
Anticancer Agent ◽  
Cisplatin Resistance ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Molecular Target ◽  
Transcriptional Level ◽  
And Control ◽  
Resistant Cells

Background: Cisplatin is an important anticancer agent in cancer chemotherapy, but when resistant cells appear, treatment becomes difficult, and the prognosis is poor. Objective: In this study, we investigated the gene expression profile in cisplatin sensitive and resistant cells, and identified the genes involved in cisplatin resistance. Methods: Comparison of gene expression profiles revealed that UBE2L6 mRNA is highly expressed in resistant cells. To elucidate whether UBE2L6 is involved in the acquisition of cisplatin resistance, UBE2L6- overexpressing cells established from cisplatin-sensitive cells and UBE2L6-silenced cells developed from cisplatin- resistant cells were generated, and the sensitivity of cisplatin was examined. Results: The sensitivity of the UBE2L6-overexpressing cells did not change compared with the control cells, but the UBE2L6-silenced cells were sensitized to cisplatin. To elucidate the mechanism of UBE2L6 in cisplatin resistance, we compared the gene expression profiles of UBE2L6-silenced cells and control cells and found that the level of ABCB6 mRNA involved in cisplatin resistance was decreased. Moreover, ABCB6 promoter activity was partially suppressed in UBE2L6-silenced cells. Conclusion: These results suggest that cisplatin-resistant cells have upregulated UBE2L6 expression and contribute to cisplatin resistance by regulating ABCB6 expression at the transcriptional level. UBE2L6 might be a molecular target that overcomes cisplatin resistance.

Influence of cellular metabolites on RNA and protein syntheses by Xanthium nuclei of different developmental phases

1986 ◽  
Vol 64 (12) ◽  
pp. 2922-2927
Author(s):  
A. Jana ◽  
S. P. Sen
Keyword(s):  
Rna Synthesis ◽  
Supernatant Fraction ◽  
Xanthium Strumarium ◽  
Low Molecular Weight ◽  
Transcriptional Level ◽  
Protein Patterns ◽  
Rna Molecules ◽  
Reproductive Tissues ◽  
Developmental Phases ◽  
Vegetative Leaf

Leaf nuclei of vegetative and reproductive plants of Xanthium strumarium L. were incubated with the postribosomal supernatant of either phase and changes at the transcriptional level were studied in homologous and heterologous combinations. In the presence of the supernatant of reproductive plants, RNA synthesis by vegetative nuclei was decreased by 25%. Reproductive nuclei were less active in RNA synthesis. Gel electrophoretic studies revealed four RNA bands in vegetative nuclei incubated with reproductive supernatant, including a fast-moving low molecular weight band that could not be detected when the "vegetative" supernatant was used. The adenine/uracil ratios of the newly synthesized RNA of vegetative nuclei treated with vegetative and reproductive supernatants were 1.46 and 1.54, respectively, compared with 1.15 and 1.04 in the reproductive nuclei. Competitive DNA–RNA hybridization experiments indicated that about 2% of the [3H]RNA synthesized by nuclei of vegetative plants in the presence of the supernatant of reproductive plants could not be beaten out by the RNA of vegetative plants. Small quantitative differences, thus, may be expected in the RNA molecules synthesized by nuclei in the presence of the supernatant fraction of vegetative and reproductive plants. The supernatant fraction of the reproductive tissues decreased the incorporation of [3H]alanine and [3H]leucine in both the buffer-soluble and acid-soluble proteins and the nuclei of vegetative plants were more active in protein synthesis. Protein patterns as studied by acrylamide gel electrophoresis revealed alterations when vegetative leaf nuclei were incubated with the supernatant of reproductive tissues.

Delivery of Cas13a/crRNA by self-degradable black phosphorus nanosheets to specifically inhibit Mcl-1 for breast cancer therapy

2020 ◽  
Vol 8 (48) ◽  
pp. 11096-11106
Author(s):  
Huahua Yue ◽  
Ru Huang ◽  
Yuanyue Shan ◽  
Da Xing
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Black Phosphorus ◽  
Endosomal Escape ◽  
Transcriptional Level ◽  
Breast Cancer Therapy

The constructed Cas13a/crRNA complex is delivered into cytoplasm by PBP via endocytosis, followed by endosomal escape based on biodegradation of the PBP, and efficiently knocked down Mcl-1 at transcriptional level for breast cancer therapy.

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