scholarly journals Control of Phosphatase and Tensin Homolog (PTEN) Gene Expression in Normal and Neoplastic Thyroid Cells

Endocrinology ◽  
2004 ◽  
Vol 145 (10) ◽  
pp. 4660-4666 ◽  
Author(s):  
Gianluca Tell ◽  
Alex Pines ◽  
Franco Arturi ◽  
Laura Cesaratto ◽  
Eileen Adamson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Transformation ◽  
Thyroid Tumor ◽  
Pten Gene ◽  
Thyroid Cell ◽  
Thyroid Cells ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Protein Levels ◽  
Tensin Homolog

Abstract The lipid phosphatase, phosphatase and tensin homolog (PTEN), is a key element in controlling cell growth and survival and has a well established role as tumor suppressor protein in many neoplasia. Several data indicate that silencing of PTEN gene expression may be relevant in follicular thyroid cell transformation. Thus, in the present study regulation of PTEN gene expression in thyroid cells was investigated. Cotransfection experiments indicated that in normal FRTL-5 rat thyroid cells, PTEN promoter activity was increased by overexpression of the transcription factor early growth response protein-1 (Egr-1). Moreover, Western blot experiments indicated that when Egr-1 expression was up-regulated by treating FRTL-5 cells with H2O2, an increase in PTEN expression was also observed. TSH induced opposite modifications on PTEN and Egr-1 protein levels. Moreover, acute or chronic TSH stimulation determined distinct effects. In fact, acute TSH stimulation (30 and 60 min) induced a decrease in PTEN, but an increase in Egr-1 protein levels. These effects were cAMP dependent; in fact, they were mimicked by forskolin. A chronic TSH treatment (5 d) stimulated PTEN protein expression, whereas Egr-1 protein was down-regulated. In contrast to normal thyroid cells, when the thyroid tumor cell lines ARO and BCPAP were exposed to H2O2, neither Egr-1 nor PTEN protein levels were increased. Acute stimulation of ARO and BCPAP cells with forskolin increased Egr-1, but not PTEN, protein levels. Therefore, thyroid tumor cell lines show alteration of PTEN gene expression regulation. RT-PCR experiments performed on human thyroid tumors showed that the absence of Egr-1 mRNA is always paralleled by the absence of PTEN mRNA. Thus, modification of the Egr-1-dependent mechanisms may play a role in the silencing of PTEN gene expression occurring during thyroid cell transformation.

In silico approach of naringin as potent phosphatase and tensin homolog (PTEN) protein agonist against prostate cancer

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Sankar Muthumanickam ◽  
Thangamariyappan Indhumathi ◽  
Pandi Boomi ◽  
Ramachandran Balajee ◽  
Jeyaraman Jeyakanthan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
In Silico ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

scholarly journals Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1719
Author(s):  
Timothy J. Lavelle ◽  
Tine Norman Alver ◽  
Karen-Marie Heintz ◽  
Patrik Wernhoff ◽  
Vegard Nygaard ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Transformation ◽  
Soft Agar ◽  
Transformation Process ◽  
Loss Of Function ◽  
Phosphatase And Tensin Homolog ◽  
Akt Activation ◽  
Transcriptional Reprogramming ◽  
Tensin Homolog ◽  
Tyrosine Receptor Kinase

The MC1R/cAMP/MITF pathway is a key determinant for growth, differentiation, and survival of melanocytes and melanoma. MITF-M is the melanocyte-specific isoform of Microphthalmia-associated Transcription Factor (MITF) in human melanoma. Here we use two melanocyte cell lines to show that forced expression of hemagglutinin (HA) -tagged MITF-M through lentiviral transduction represents an oncogenic insult leading to consistent cell transformation of the immortalized melanocyte cell line Hermes 4C, being a melanocortin-1 receptor (MC1R) compound heterozygote, while not causing transformation of the MC1R wild type cell line Hermes 3C. The transformed HA-tagged MITF-M transduced Hermes 4C cells form colonies in soft agar and tumors in mice. Further, Hermes 4C cells display increased MITF chromatin binding, and transcriptional reprogramming consistent with an invasive melanoma phenotype. Mechanistically, forced expression of MITF-M drives the upregulation of the AXL tyrosine receptor kinase (AXL), with concomitant downregulation of phosphatase and tensin homolog (PTEN), leading to increased activation of the PI3K/AKT pathway. Treatment with AXL inhibitors reduces growth of the transformed cells by reverting AKT activation. In conclusion, we present a model system of melanoma development, driven by MITF-M in the context of MC1R loss of function, and independent of UV exposure. This model provides a basis for further studies of critical changes in the melanocyte transformation process.

Reduced PTEN Protein Expression and Its Prognostic Implications in Canine and Feline Mammary Tumors

2009 ◽  
Vol 46 (5) ◽  
pp. 860-868 ◽  
Author(s):  
L. Ressel ◽  
F. Millanta ◽  
E. Caleri ◽  
V. M. Innocenti ◽  
A. Poli
Keyword(s):  
Protein Expression ◽  
Lymphatic Vessel ◽  
Mammary Tumors ◽  
Lymphatic Vessel Invasion ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Mammary Carcinomas ◽  
Tensin Homolog ◽  
Vessel Invasion ◽  
Distant Organ

Phosphatase and tensin homolog (PTEN) belongs to the group of gatekeeper tumor suppressor genes and is involved in multiple mechanisms leading to cellular defense against neoplastic transformation and progression. Twenty-four dogs and 17 cats were submitted to a 2-year follow-up study, and clinicopathologic features were recorded and compared with immunohistochemical PTEN staining. PTEN-negative status occurred in 33% of canine and 76% of feline mammary carcinomas. In canine mammary carcinomas, there was a significant ( P < .05) correlation between loss of PTEN protein expression and simple carcinoma histotype, lymphatic vessel invasion, lymph node metastases, distant organ metastases, tumor dedifferentiation, tumor recurrence, and shorter overall survival. In feline mammary tumors, a significant correlation between loss of PTEN protein expression and lymphatic vessel invasion was found. Loss of PTEN expression could be a useful prognostic marker in canine mammary carcinomas.

scholarly journals Induction of Apoptotic Genes by a p73-Phosphatase and Tensin Homolog (p73-PTEN) Protein Complex in Response to Genotoxic Stress

2011 ◽  
Vol 286 (42) ◽  
pp. 36631-36640 ◽  
Author(s):  
Jason A. Lehman ◽  
David L. Waning ◽  
Christopher N. Batuello ◽  
Rocky Cipriano ◽  
Madhavi P. Kadakia ◽  
...  
Keyword(s):  
Protein Complex ◽  
Genotoxic Stress ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Apoptotic Genes

scholarly journals The molecular dynamics of long noncoding RNA control of transcription in PTEN and its pseudogene

2017 ◽  
Vol 114 (37) ◽  
pp. 9942-9947 ◽  
Author(s):  
Nicholas Lister ◽  
Galina Shevchenko ◽  
James L. Walshe ◽  
Jessica Groen ◽  
Per Johnsson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Structure ◽  
Noncoding Rna ◽  
Dna Methyltransferase ◽  
Regulation Of Gene Expression ◽  
Control Of Gene Expression ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Sequence Components ◽  
Antisense Lncrnas

RNA has been found to interact with chromatin and modulate gene transcription. In human cells, little is known about how long noncoding RNAs (lncRNAs) interact with target loci in the context of chromatin. We find here, using the phosphatase and tensin homolog (PTEN) pseudogene as a model system, that antisense lncRNAs interact first with a 5′ UTR-containing promoter-spanning transcript, which is then followed by the recruitment of DNA methyltransferase 3a (DNMT3a), ultimately resulting in the transcriptional and epigenetic control of gene expression. Moreover, we find that the lncRNA and promoter-spanning transcript interaction are based on a combination of structural and sequence components of the antisense lncRNA. These observations suggest, on the basis of this one example, that evolutionary pressures may be placed on RNA structure more so than sequence conservation. Collectively, the observations presented here suggest a much more complex and vibrant RNA regulatory world may be operative in the regulation of gene expression.

scholarly journals Pax-8 protein levels regulate thyroglobulin gene expression

1998 ◽  
Vol 21 (3) ◽  
pp. 347-354 ◽  
Author(s):  
D Fabbro ◽  
L Pellizzari ◽  
F Mercuri ◽  
G Tell ◽  
G Damante
Keyword(s):  
Promoter Activity ◽  
Expression Vector ◽  
Cell Types ◽  
Thyroid Cell ◽  
Critical Approach ◽  
Thyroid Cells ◽  
Protein Levels ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Thyroglobulin Gene

Pax proteins are transcription factors that control differentiation of several cell types. In adult organisms Pax-8 is expressed in the follicular thyroid cell where it interacts with sequences of thyroglobulin and thyroperoxidase promoters. In this study, we provide evidence indicating that Pax-8 protein levels regulate thyroglobulin gene transcription. The most critical approach consisted in increasing Pax-8 protein levels by transfecting thyroid cells with a Pax-8 expression vector. In this situation the thyroglobulin promoter transcriptional activity was significantly increased with respect to untransfected cells. In contrast, the transfection of thyroid transcription factor-1 (TTF-1) expression vector causes a modest decrease of thyroglobulin promoter activity, rather than an increase. Northern blots of human papillary cancers reveal a significant correlation between Pax-8 and thyroglobulin mRNAs. Gel-retardation assays suggest that the mechanism by which the Pax-8 protein levels modulate thyroglobulin promoter activity may occur through competition with TTF-1 for a common binding site. Since we also demonstrate that Pax-8 expression is subjected to TSH control, our data strongly suggest that Pax-8 protein levels could represent an important determinant for the regulation of thyroid cells.

scholarly journals Molecular Analysis of AFP and HSA Interactions with PTEN Protein

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Mingyue Zhu ◽  
Bo Lin ◽  
Peng Zhou ◽  
Mengsen Li
Keyword(s):  
Molecular Docking ◽  
Molecular Mechanisms ◽  
Docking Study ◽  
Phosphatidylinositol 3 Kinase ◽  
Molecular Docking Study ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Significant Homology ◽  
Modeling Data

Human cytoplasmic alpha-fetoprotein (AFP) has been classified as a member of the albuminoid gene family. The protein sequence of AFP has significant homology to that of human serum albumin (HSA), but its biological characteristics are vastly different from HSA. The AFP functions as a regulator in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, but HSA plays a key role as a transport protein. To probe their molecular mechanisms, we have applied colocalization, coimmunoprecipitation (co-IP), and molecular docking approaches to analyze the differences between AFP and HSA. The data from colocalization and co-IP displayed a strong interaction between AFP and PTEN (phosphatase and tensin homolog), demonstrating that AFP did bind to PTEN, but HSA did not. The molecular docking study further showed that the AFP domains I and III could contact with PTEN.In siliconsubstitutions of AFP binding site residues at position 490M/K and 105L/R corresponding to residues K490 and R105 in HSA resulted in steric clashes with PTEN residues R150 and K46, respectively. These steric clashes may explain the reason why HSA cannot bind to PTEN. Ultimately, the experimental results and the molecular modeling data from the interactions of AFP and HSA with PTEN will help us to identify targets for designing drugs and vaccines against human hepatocellular carcinoma.

scholarly journals Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor

2021 ◽  
Vol 12 ◽  
Author(s):  
Tianyu He ◽  
Xiaoyun Zhang ◽  
Jianyu Hao ◽  
Shigang Ding
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Malignant Tumors ◽  
Biological Effects ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
And Migration

The Phosphatase and tensin homolog (PTEN) gene is one of the most important tumor suppressor genes, which acts through its unique protein phosphatase and lipid phosphatase activity. PTEN protein is widely distributed and exhibits complex biological functions and regulatory modes. It is involved in the regulation of cell morphology, proliferation, differentiation, adhesion, and migration through a variety of signaling pathways. The role of PTEN in malignant tumors of the digestive system is well documented. Recent studies have indicated that PTEN may be closely related to many other benign processes in digestive organs. Emerging evidence suggests that PTEN is a potential therapeutic target in the context of several non-neoplastic diseases of the digestive tract. The recent discovery of PTEN isoforms is expected to help unravel more biological effects of PTEN in non-neoplastic digestive diseases.

scholarly journals A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

2018 ◽  
Author(s):  
Taylor L. Mighell ◽  
Sara Evans-Dutson ◽  
Brian j. O’Roak
Keyword(s):  
Phosphatase Activity ◽  
Autism Spectrum ◽  
Saturation Mutagenesis ◽  
Single Amino Acid ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
Functional Scores

ABSTRACTPhosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). These data uncovered novel insights into PTEN protein structure, biochemistry, and mutation tolerance. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD associated mutations generally had less severe fitness scores relative to PHTS associated mutations (p = 7.16×10-5) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data.

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