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.

scholarly journals A Protein with Similarity to PTEN Regulates Aggregation Territory Size by Decreasing Cyclic AMP Pulse Size during Dictyostelium discoideum Development

2008 ◽  
Vol 7 (10) ◽  
pp. 1758-1770 ◽  
Author(s):  
Yitai Tang ◽  
Richard H. Gomer
Keyword(s):  
Cyclic Amp ◽  
Group Size ◽  
Actin Polymerization ◽  
Insertional Mutagenesis ◽  
Territory Size ◽  
Camp Phosphodiesterase ◽  
Phosphatase And Tensin Homolog ◽  
Akt Activation ◽  
Tensin Homolog ◽  
Eukaryotic Organisms

ABSTRACT An interesting but largely unanswered biological question is how eukaryotic organisms regulate the size of multicellular tissues. During development, a lawn of Dictyostelium cells breaks up into territories, and within the territories the cells aggregate in dendritic streams to form groups of ∼20,000 cells. Using random insertional mutagenesis to search for genes involved in group size regulation, we found that an insertion in the cnrN gene affects group size. Cells lacking CnrN (cnrN −) form abnormally small groups, which can be rescued by the expression of exogenous CnrN. Relayed pulses of extracellular cyclic AMP (cAMP) direct cells to aggregate by chemotaxis to form aggregation territories and streams. cnrN − cells overaccumulate cAMP during development and form small territories. Decreasing the cAMP pulse size by treating cnrN − cells with cAMP phosphodiesterase or starving cnrN − cells at a low density rescues the small-territory phenotype. The predicted CnrN sequence has similarity to phosphatase and tensin homolog (PTEN), which in Dictyostelium inhibits cAMP-stimulated phosphatidylinositol 3-kinase signaling pathways. CnrN inhibits cAMP-stimulated phosphatidylinositol 3,4,5-trisphosphate accumulation, Akt activation, actin polymerization, and cAMP production. Our results suggest that CnrN is a protein with some similarities to PTEN and that it regulates cAMP signal transduction to regulate territory size.

scholarly journals Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Inhibition by 4-Hydroxynonenal Leads to Increased Akt Activation in Hepatocytes

2011 ◽  
Vol 79 (6) ◽  
pp. 941-952 ◽  
Author(s):  
Colin T. Shearn ◽  
Rebecca L. Smathers ◽  
Benjamin J. Stewart ◽  
Kristofer S. Fritz ◽  
James J. Galligan ◽  
...  
Keyword(s):  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Akt Activation ◽  
Tensin Homolog ◽  
Pten Inhibition

PTEN-Related Overgrowth Syndromes

2019 ◽  
pp. 163-186
Author(s):  
Lamis Yehia ◽  
Joanne Ngeow ◽  
Charis Eng
Keyword(s):  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Treatment Strategies ◽  
Suppressor Gene ◽  
Cowden Syndrome ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Cell Growth And Proliferation

Individuals carrying germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) may present with diverse clinical phenotypes, grouped under the term of PTEN hamartoma tumor syndrome (PHTS). This chapter will focus on two PHTS conditions: Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome. The first condition is an autosomal dominant disorder characterized by macrocephaly, intestinal hamartomatous polyposis, vascular malformations, lipomas, hemangiomas, and genital freckling. Other features include developmental delay, hypotonia, and scoliosis. Cowden syndrome is also an autosomal dominant disorder, mainly characterized by multiple hamartomas and high risk of breast, thyroid, and other cancers. PTEN encodes the main inhibitor of the PI3K-AKT pathway, regulating cell growth and proliferation, and protein synthesis. Therefore, germline loss-of-function mutations in this gene lead to excessive growth, particularly affecting connective tissues. Detection of PTEN mutations is critical for clinical management and treatment strategies.

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.

scholarly journals LINC00470 Stimulates Methylation of PTEN to Facilitate the Progression of Endometrial Cancer by Recruiting DNMT3a Through MYC

2021 ◽  
Vol 11 ◽  
Author(s):  
Tiezhong Yi ◽  
Yicun Song ◽  
Lingling Zuo ◽  
Siyun Wang ◽  
Jintian Miao
Keyword(s):  
Endometrial Cancer ◽  
Tube Formation ◽  
Loss Of Function ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Kaplan Meier ◽  
Ec Cells ◽  
Non Coding Rnas

ObjectivesIncreasing researches emphasize the importance of long non-coding RNAs (lncRNAs) in the development of endometrial cancer (EC). There is wide recognition that LINC00470 is a critical participant in the tumorigenesis of cancers such as gastric cancer and glioblastoma, but its possible effects on EC progression remain to be explored.MethodsWe collected EC tissues and cells, where the expression of LINC00470 was determined, and followed by the Kaplan-Meier analysis of EC patient survival. We next examined the effect of LINC00470 and phosphatase and tensin homolog (PTEN) on EC cell migration, invasion, tube formation in vitro, and angiogenesis in mice xenografted with tumor after gain- or loss-of-function treatments. RNA pull-down, Co-IP, and ChIP experiments were performed to analyze the targeting relationships among LINC00470, MYC and DNMT3a.ResultsLINC00470 was aberrantly upregulated in EC and its high expression correlated to prognosis of EC patients. LINC00470 promoted invasiveness, migration, and angiogenesis of EC cells, and facilitated tumorigenesis and metastasis in vivo, but those effects were reversed by up-regulating PTEN. Functionally, LINC00470 bound to MYC in EC and that LINC00470 stimulated the binding of MYC to DNMT3a, and thus recruited DNMT3a through MYC to promote PTEN methylation.ConclusionsOur findings revealed that LINC00470 stimulated PTEN methylation to inhibit its expression by MYC-induced recruitment of DNMT3a, thus aggravating EC.

scholarly journals Discovery and functional characterization of a neomorphic PTEN mutation

2015 ◽  
Vol 112 (45) ◽  
pp. 13976-13981 ◽  
Author(s):  
Helio A. Costa ◽  
Michael G. Leitner ◽  
Martin L. Sos ◽  
Angeliki Mavrantoni ◽  
Anna Rychkova ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Functional Characterization ◽  
Genetic Alterations ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Phosphatase And Tensin Homolog ◽  
Pten Loss ◽  
Tensin Homolog ◽  
Cancer Tumor

Although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles. Here, we use whole genome sequencing of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein. We demonstrate that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. These findings suggest that mutationally modified PTEN can actively contribute to well-defined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These results demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy.

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