scholarly journals The complex regulation of NIS expression and activity in thyroid and extrathyroidal tissues

2021 ◽  
Author(s):  
Garcilaso Riesco-Eizaguirre ◽  
Pilar Santisteban ◽  
Antonio De la Vieja
Keyword(s):  
Plasma Membrane ◽  
Regulatory Elements ◽  
Fine Tuning ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Transcriptional Regulatory Elements ◽  
Iodide Transport ◽  
Theranostic Agent ◽  
Transcriptional Regulatory ◽  
And Function

The sodium iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues. NIS-mediated iodide uptake plays a pivotal role in the biosynthesis of thyroid hormones, of which iodide is an essential constituent. For 80 years radioiodide has been used for the diagnosis and treatment of thyroid cancer, a successful theranostic agent that is extending its use to extrathyroidal malignancies. The purpose of this review is to focus on the most recent findings regarding the mechanisms that regulate NIS both in thyroid and extra-thyroidal tissues. Among other issues, we discuss the different transcriptional regulatory elements that govern NIS transcription in different tissues, the epigenetic modifications that regulate its expression and the role that miRNAs play in fine tuning NIS after being transcribed. A review on the hormones, cytokines, and iodide itself that regulate NIS is provided. We also review the present stage of understanding NIS dysregulation in cancer, occupied mainly by convergent signaling pathways and by new insights in the route that NIS follows through different subcellular compartments to the plasma membrane. Furthermore, we cover NIS distribution and function in the increasing number of extrathyroidal tissues that express the symporter, as well as the role that NIS plays in tumor progression independently of its transport activity.

scholarly journals Modulation of sodium iodide symporter expression and function by LY294002, Akti-1/2 and Rapamycin in thyroid cells

2012 ◽  
Vol 19 (3) ◽  
pp. 291-304 ◽  
Author(s):  
Yu-Yu Liu ◽  
Xiaoli Zhang ◽  
Matthew D Ringel ◽  
Sissy M Jhiang
Keyword(s):  
Sodium Iodide Symporter ◽  
Efflux Rate ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Thyroid Cancers ◽  
Protein Levels ◽  
Iodide Transport ◽  
Pi3k Inhibition ◽  
And Function ◽  
Selective Increase

The selective increase of Na+/I−symporter (NIS)-mediated active iodide uptake in thyroid cells allows the use of radioiodine I131for diagnosis and targeted treatment of thyroid cancers. However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function. As PI3K signaling is overactivated in many thyroid tumors, we investigated the effects of inhibitors for PI3K, Akt, or mTORC1 as well as their interplay on NIS modulation in thyroid cells under chronic TSH stimulation. PI3K inhibition by LY294002 increased NIS-mediated radioiodide uptake (RAIU) mainly through upregulation of NIS expression, however, mTORC1 inhibition by Rapamycin did not increase NIS-mediated RAIU despite increased NIS protein levels. In comparison, Akt inhibition by Akti-1/2 did not increase NIS protein levels, yet markedly increased NIS-mediated RAIU by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effects of Akti-1/2 on NIS-mediated RAIU are not detected in nonthyroid cells, implying that Akti-1/2 or its derivatives may represent potential pharmacological reagents to selectively increase thyroidal radioiodine accumulation and therapeutic efficacy.

Identification of transcriptional elements within the long terminal repeat of Rous sarcoma virus

1983 ◽  
Vol 3 (10) ◽  
pp. 1834-1845
Author(s):  
G M Gilmartin ◽  
J T Parsons
Keyword(s):  
Long Terminal Repeat ◽  
Virus Replication ◽  
Rous Sarcoma Virus ◽  
Regulatory Elements ◽  
Terminal Repeat ◽  
Tata Box ◽  
Transcriptional Regulatory Elements ◽  
Rous Sarcoma ◽  
Transcriptional Regulatory ◽  
Sarcoma Virus

Transcriptional regulatory elements within the Rous sarcoma virus long terminal repeat were examined by the construction of a series of deletions and small insertions within the U3 region of the long terminal repeat. The analysis of these mutations in chicken embryo cells and COS cells permitted the identification of important transcriptional regulatory elements. Sequences within the region 31 to 18 base pairs upstream of the RNA cap site (-31 to -18), encompassing a TATA box-like sequence, function in the selection of the correct site of transcription initiation and, in addition, augment the efficiency of transcription. These sequences are essential for virus replication. Sequences within the region -79 to -59, overlapping a CAAT box-like sequence, are not required for virus replication and have no obvious effect on viral RNA transcription in the presence of an intact TATA box. However, in mutants lacking a functional TATA sequence, mutations in this region serve to decrease the efficiency of correct transcriptional initiation events.

scholarly journals Expression and function of the novel proto-oncogene PBF in thyroid cancer: a new target for augmenting radioiodine uptake

2011 ◽  
Vol 210 (2) ◽  
pp. 157-163 ◽  
Author(s):  
Vicki E Smith ◽  
Jayne A Franklyn ◽  
Christopher J McCabe
Keyword(s):  
Thyroid Cancer ◽  
Current Data ◽  
Subcellular Localisation ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Radioiodine Uptake ◽  
Novel Target ◽  
And Function

Pituitary tumor-transforming gene (PTTG)-binding factor (PBF; PTTG1IP) was initially identified through its interaction with the human securin, PTTG. Like PTTG, PBF is upregulated in multiple endocrine tumours including thyroid cancer. PBF is believed to induce the translocation of PTTG into the cell nucleus where it can drive tumourigenesis via a number of different mechanisms. However, an independent transforming ability has been demonstrated both in vitro and in vivo, suggesting that PBF is itself a proto-oncogene. Studied in only a limited number of publications to date, PBF is emerging as a protein with a growing repertoire of roles. Recent data suggest that PBF possesses a complex multifunctionality in an increasing number of tumour settings. For example, PBF is upregulated by oestrogen and mediates oestrogen-stimulated cell invasion in breast cancer cells. In addition to a possible role in the induction of thyroid tumourigenesis, PBF overexpression in thyroid cancers inhibits iodide uptake. PBF has been shown to repress sodium iodide symporter (NIS) activity by transcriptional regulation of NIS expression through the human NIS upstream enhancer and further inhibits iodide uptake via a post-translational mechanism of NIS governing subcellular localisation. This review discusses the current data describing PBF expression and function in thyroid cancer and highlights PBF as a novel target for improving radioiodine uptake and thus prognosis in thyroid cancer.

scholarly journals Identification of positive and negative transcriptional regulatory elements of the rabbit angiotensin-converting enzyme gene

1994 ◽  
Vol 22 (7) ◽  
pp. 1194-1201 ◽  
Author(s):  
Tauqir Y. Goraya ◽  
Sean P. Kessler ◽  
Ravi S. Kumar ◽  
Janice Douglas ◽  
Ganes C. Sen
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Regulatory Elements ◽  
Angiotensin Converting Enzyme Gene ◽  
Converting Enzyme ◽  
Enzyme Gene ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory

scholarly journals Discovering Transcriptional Regulatory Elements From Run‐On and Sequencing Data Using the Web‐Based dREG Gateway

2018 ◽  
Vol 66 (1) ◽  
Author(s):  
Tinyi Chu ◽  
Zhong Wang ◽  
Shao‐Pei Chou ◽  
Charles G. Danko
Keyword(s):  
Regulatory Elements ◽  
Sequencing Data ◽  
Web Based ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory ◽  
The Web

scholarly journals Systematic dissection of transcriptional regulatory networks by genome-scale and single-cell CRISPR screens

2021 ◽  
Vol 7 (27) ◽  
pp. eabf5733
Author(s):  
Rui Lopes ◽  
Kathleen Sprouffske ◽  
Caibin Sheng ◽  
Esther C. H. Uijttewaal ◽  
Adriana Emma Wesdorp ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regulatory Networks ◽  
Essential Role ◽  
Regulatory Elements ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory ◽  
Functional Relevance ◽  
Genome Scale ◽  
Transcription Program

Millions of putative transcriptional regulatory elements (TREs) have been cataloged in the human genome, yet their functional relevance in specific pathophysiological settings remains to be determined. This is critical to understand how oncogenic transcription factors (TFs) engage specific TREs to impose transcriptional programs underlying malignant phenotypes. Here, we combine cutting edge CRISPR screens and epigenomic profiling to functionally survey ≈15,000 TREs engaged by estrogen receptor (ER). We show that ER exerts its oncogenic role in breast cancer by engaging TREs enriched in GATA3, TFAP2C, and H3K27Ac signal. These TREs control critical downstream TFs, among which TFAP2C plays an essential role in ER-driven cell proliferation. Together, our work reveals novel insights into a critical oncogenic transcription program and provides a framework to map regulatory networks, enabling to dissect the function of the noncoding genome of cancer cells.

scholarly journals Elucidating the Regulatory Elements for Transcription Termination and Posttranscriptional Processing in the Streptomyces clavuligerus Genome

mSystems ◽  
2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Soonkyu Hwang ◽  
Namil Lee ◽  
Donghui Choe ◽  
Yongjae Lee ◽  
Woori Kim ◽  
...  
Keyword(s):  
Secondary Metabolite ◽  
Transcription Termination ◽  
Gene Clusters ◽  
Streptomyces Clavuligerus ◽  
Regulatory Elements ◽  
Regulation Of Transcription ◽  
Content Type ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory ◽  
Posttranscriptional Processing

ABSTRACT Identification of transcriptional regulatory elements in the GC-rich Streptomyces genome is essential for the production of novel biochemicals from secondary metabolite biosynthetic gene clusters (smBGCs). Despite many efforts to understand the regulation of transcription initiation in smBGCs, information on the regulation of transcription termination and posttranscriptional processing remains scarce. In this study, we identified the transcriptional regulatory elements in β-lactam antibiotic-producing Streptomyces clavuligerus ATCC 27064 by determining a total of 1,427 transcript 3′-end positions (TEPs) using the term-seq method. Termination of transcription was governed by three classes of TEPs, of which each displayed unique sequence features. The data integration with transcription start sites and transcriptome data generated 1,648 transcription units (TUs) and 610 transcription unit clusters (TUCs). TU architecture showed that the transcript abundance in TU isoforms of a TUC was potentially affected by the sequence context of their TEPs, suggesting that the regulatory elements of TEPs could control the transcription level in additional layers. We also identified TU features of a xenobiotic response element (XRE) family regulator and DUF397 domain-containing protein, particularly showing the abundance of bidirectional TEPs. Finally, we found that 189 noncoding TUs contained potential cis- and trans-regulatory elements that played a major role in regulating the 5′ and 3′ UTR. These findings highlight the role of transcriptional regulatory elements in transcription termination and posttranscriptional processing in Streptomyces sp. IMPORTANCE Streptomyces sp. is a great source of bioactive secondary metabolites, including antibiotics, antifungal agents, antiparasitic agents, immunosuppressant compounds, and other drugs. Secondary metabolites are synthesized via multistep conversions of the precursor molecules from primary metabolism, governed by multicomplex enzymes from secondary metabolite biosynthetic gene clusters. As their production is closely related with the growth phase and dynamic cellular status in response to various intra- and extracellular signals, complex regulatory systems tightly control the gene expressions related to secondary metabolism. In this study, we determined genome-wide transcript 3′-end positions and transcription units in the β-lactam antibiotic producer Streptomyces clavuligerus ATCC 27064 to elucidate the transcriptional regulatory elements in transcription termination and posttranscriptional processing by integration of multiomics data. These unique features, such as transcript 3′-end sequence, potential riboregulators, and potential 3′-untranslated region (UTR) cis-regulatory elements, can be potentially used to design engineering tools that can regulate the transcript abundance of genes for enhancing secondary metabolite production.

scholarly journals Prediction and identification of transcriptional regulatory elements at the lung cancer‑specific DKK1 locus

2018 ◽  
Author(s):  
Yan Gao ◽  
Xian Du ◽  
Jing Zeng ◽  
Ruimin Wu ◽  
Yijia Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Regulatory Elements ◽  
Transcriptional Regulatory Elements ◽  
Transcriptional Regulatory

scholarly journals Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival

2012 ◽  
Vol 199 (7) ◽  
pp. 1145-1158 ◽  
Author(s):  
Hyung Joon Kim ◽  
Vikram Prasad ◽  
Seok-Won Hyung ◽  
Zang Hee Lee ◽  
Sang-Won Lee ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Bone Mass ◽  
Osteoclast Differentiation ◽  
Premenopausal Women ◽  
Fine Tuning ◽  
Bone Homeostasis ◽  
Regulatory Loop ◽  
And Function

The precise regulation of Ca2+ dynamics is crucial for proper differentiation and function of osteoclasts. Here we show the involvement of plasma membrane Ca2+ ATPase (PMCA) isoforms 1 and 4 in osteoclastogenesis. In immature/undifferentiated cells, PMCAs inhibited receptor activator of NF-κB ligand–induced Ca2+ oscillations and osteoclast differentiation in vitro. Interestingly, nuclear factor of activated T cell c1 (NFATc1) directly stimulated PMCA transcription, whereas the PMCA-mediated Ca2+ efflux prevented NFATc1 activation, forming a negative regulatory loop. PMCA4 also had an anti-osteoclastogenic effect by reducing NO, which facilitates preosteoclast fusion. In addition to their role in immature cells, increased expression of PMCAs in mature osteoclasts prevented osteoclast apoptosis both in vitro and in vivo. Mice heterozygous for PMCA1 or null for PMCA4 showed an osteopenic phenotype with more osteoclasts on bone surface. Furthermore, PMCA4 expression levels correlated with peak bone mass in premenopausal women. Thus, our results suggest that PMCAs play important roles for the regulation of bone homeostasis in both mice and humans by modulating Ca2+ signaling in osteoclasts.

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