PTEN interacts with metal-responsive transcription factor 1 and stimulates its transcriptional activity

Lin, Ming-Yi; Liu, Ya-Chuan; Tam, Ming F.; Lu, Yu-Ju; Hsieh, Ya-Ting; Lin, Li‐Yen

doi:10.1042/bj20111257

Cited by 15 publications

(18 citation statements)

References 49 publications

(74 reference statements)

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“…Recent data, however, support important biological roles for nuclear PTEN through direct interactions with nuclear factors and independent of its phosphatase activity50 or as a nuclear protein phosphatase that directly targets transcription factors to activate them4651. To determine if PTEN regulates SRF through interaction between the proteins, reciprocal co-immunoprecipitation (co-IP) assays were performed.…”

Section: Resultsmentioning

confidence: 99%

“…Since SM gene expression is under direct transcriptional control by SRF, the mechanism underlying PTEN's regulation of the SMC differentiation program remained unclear. Emerging data in other cell systems support a role for nuclear PTEN both in a phosphatase-dependent and -independent manner thereby uncovering a function for PTEN independent of its cytoplasmic Akt-antagonizing effects454647484950515253. However, there is no information regarding the biological significance of nuclear PTEN in SMCs.…”

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confidence: 99%

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Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation

et al. 2016

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Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN–SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation

et al. 2016

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“…Association of PTEN with several transcription factors, including Sp1, MTF1, CREB in the nucleus is known to regulate the expression of multiple genes [27,29,53]. Therefore, we tested whether PTEN physically associates with the E2F1 protein via co-immunoprecipitation (co-IP) experiments.…”

Section: Pten-4a Physically Interacts With E2f1 Protein and At E2f1 Dmentioning

confidence: 99%

“…PTEN also associates with DNA damage repair proteins such as Rad51 and Rad52 in response to DNA damage [19,[22][23][24][25][26]. While PTEN is not known to bind DNA, it associates with several transcription factors such as MTF1, SRF, CREB, MAF1, histones and chromatin remodelers to control the expression of selected genes [27][28][29][30][31][32]. PTEN exerts an inhibitory effect on the cell cycle [33][34][35][36], however the effect of PTEN phosphorylation on different phases of the cell cycle is only recently emerging.…”

Section: Introductionmentioning

confidence: 99%

PTEN Physically Interacts with and Regulates E2F1-mediated Transcription in Lung Cancer

Malaney¹,

Palumbo²,

Semidey-Hurtado³

et al. 2018

Cell Cycle

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PTEN phosphorylation at its C-terminal (C-tail) serine/threonine cluster negatively regulates its tumor suppressor function. However, the consequence of such inhibition and its downstream effects in driving lung cancer remain unexplored. Herein, we ascertain the molecular mechanisms by which phosphorylation compromises PTEN function, contributing to lung cancer. Replacement of the serine/threonine residues with alanine generated PTEN-4A, a phosphorylation-deficient PTEN mutant, which suppressed lung cancer cell proliferation and migration. PTEN-4A preferentially localized to the nucleus where it suppressed E2F1-mediated transcription of cell cycle genes. PTEN-4A physically interacted with the transcription factor E2F1 and associated with chromatin at gene promoters with E2F1 DNA-binding sites, a likely mechanism for its transcriptional suppression function. Deletion analysis revealed that the C2 domain of PTEN was indispensable for suppression of E2F1-mediated transcription. Further, we uncovered cancer-associated C2 domain mutant proteins that had lost their ability to suppress E2F1-mediated transcription, supporting the concept that these mutations are oncogenic in patients. Consistent with these findings, we observed increased PTEN phosphorylation and reduced nuclear PTEN levels in lung cancer patient samples establishing phosphorylation as a bona fide inactivation mechanism for PTEN in lung cancer. Thus, use of small molecule inhibitors that hinder PTEN phosphorylation is a plausible approach to activate PTEN function in the treatment of lung cancer. Abbreviations AKT V-Akt Murine Thymoma Viral Oncogene CA Cancer adjacent CDK1 Cyclin dependent kinase 1 CENPC-C Centromere Protein C ChIP Chromatin Immunoprecipitation co-IP Co-immunoprecipitation COSMIC Catalog of Somatic Mutations In Cancer CREB cAMP Responsive Element Binding Protein C-tail Carboxy terminal tail E2F1 E2F Transcription Factor 1 ECIS Electric Cell-substrate Impedance Sensing EGFR Epidermal Growth Factor Receptor GSI Gamma Secretase Inhibitor HDAC1 Histone Deacetylase 1 HP1 Heterochromatin protein 1 KAP1/TRIM28 KRAB-Associated Protein 1/Tripartite Motif Containing 28 MAF1 Repressor of RNA polymerase III transcription MAF1 homolog MCM2 Minichromosome Maintenance Complex Component 2 miRNA micro RNA MTF1 Metal-Regulatory Transcription Factor 1 PARP Poly(ADP-Ribose) Polymerase PD-1 Programmed Cell Death 1 PD-L1 Programmed Cell Death 1 Ligand 1 PI3K Phosphatidylinositol-4,5-Bisphosphate 3-Kinase PLK Polo-like Kinase pPTEN Phosphorylated PTEN PTEN Phosphatase and Tensin Homolog deleted on chromosome ten PTM Post Translational Modification Rad51 RAD51 Recombinase Rad52 RAD52 Recombinase RPA1 Replication protein A SILAC Stable Isotope Labeling with Amino Acids in Cell Culture SRF Serum Response Factor TKI Tyrosine Kinase inhbitors TMA Tissue Microarray TOP2A DNA Topoisomerase 2A.

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“…(7) Furthermore, MT gene expression is induced by heavy metal ions through several mechanisms that facilitate MTF-1 transport to the nucleus and induce DNA binding, where it exerts an effect on gene transcription such as MT. (23) The higher expression of both genes in groups IV and V than the control group as well as the CNCreceived group may be due to the carcinogenic effect of DAB which generate free radicals (ROS and RNS) as well as oxidative stress. Whereas, comparing with cancer group, the genes expression was statistically low in group IV (pretreated group) and group V but still higher than that of the control group.…”

Section: Discussionmentioning

confidence: 99%

Effects of Copper Nicotinate Complex on Renal Metallothionein and Metal-responsive Transcription Factor 1 Genes Expression During 4-Dimethylaminoazobenzene Exposure in Rats

Hussein

Yehia

2015

Journal of High Institute of Public Health

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Background: The expression of MT genes in animal's body is rapidly elevated in response to metal and agents which cause oxidative stress and/or inflammation. The MTF-1 plays an essential role in regulating transcription of MT gene in response to metal ions and oxidative stress. Metalloviatamin complex was found to exhibit anti-tumor and anti-inflammatory activity, cytoprotective effect and reduces oxidative stress. Objectives: The study was designed to evaluate effects of a daily dose of copper nicotinate complex (CNC) on metallothionein-III (MT-III) and metal-responsive transcription factor -1 (MTF-1) expression during 4-dimethylaminoazobenzene (DAB) exposure. Methods: Ninety rats were divided into five groups. Group I rats were fed on standard diet and was considered the control group; group II rats were fed on standard diet containing DAB (0.06g/100g diet daily) for six months; group III rats received CNC dissolved in saline solution (1mg/kg body weight daily) for six months; group IV rats were pretreated with CNC one month before DAB; group V rats were post treated with CNC after one month of starting feeding on DAB. MT-III and MTF-1 genes expression was assayed by PCR. Renal histopathological changes were examined by light microscopy. Results: Genes expression in all groups was statistically high at all time intervals as compared with control group, while it was decreased in groups III, IV and V as compared to cancer group (II). In group IV and V, the genes expression was statistically increased as compared with group III. MT expression in control group declined with age, while it was higher at 6 th month than 2 nd and 4 th month in group II. MTF-1 expression was increased at 4 th month followed by decrease at 6 th month in all studied groups. These results were confirmed by histopathological change. There was an increase in pyknotic and necrotic nuclei in tubular epithelial cells and a mild dilatation of renal tubules. Conclusion: Scavenging ROS during DAB-induced oxidative stress may be the major role of MT. CNC causes a partial improvement in the genes expression as well as renal tubules, so CNC may be a promising candidate used for protection against oxidative stress.

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PTEN interacts with metal-responsive transcription factor 1 and stimulates its transcriptional activity

Cited by 15 publications

References 49 publications

Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation

Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation

PTEN Physically Interacts with and Regulates E2F1-mediated Transcription in Lung Cancer

Effects of Copper Nicotinate Complex on Renal Metallothionein and Metal-responsive Transcription Factor 1 Genes Expression During 4-Dimethylaminoazobenzene Exposure in Rats

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