Functional properties of PTEN and PTEN mutants in U87MG glioblastoma cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Nicholas Schurch
PROVIDER: E-MTAB-989 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. Whilst the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Using knock-in (KI) mice harbouring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. The dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN-loss driven cancers.
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Project description:We intended to elucidate the underlying mechanism of PTEN-Nedd8 in tumorigenesis. So, we firstly employed affinity purification and mass spectrometry to interrogate PTEN-Nedd8 interactome in nucleus.
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Project description:Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are largely unknown. Here we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in its phosphatase-independent manner, and identify262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. Especially, the exon-2b exclusion of GOLGA2 contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors, Brefeldin A and Golgicide A. Given that many cancers lack PTEN expression, our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers.
2018-10-18 | PXD009681 | Pride
Project description:MicroRNA profiling in Pten knockout mouse thymus cells. microRNAs (miRs) are short noncoding RNAs of 20â22 nucleotides that function to regulate gene expression at the posttranscriptional level. They play fundamental roles in the regulation of cellular proliferation, differentiation, and apoptosis. miRs are dysregulated in many types of cancer, including T-ALL (T cell lymphoblastic leukemia). miRs can function as oncogenes, favoring the initiation and progression of cancers, or as tumor suppressors, preventing tumorigenesis. The biological functions of miRs in T-ALL are largely unknown. In human T-ALL patients, recurrent mutations in the Phosphatase and tensin homolog (PTEN) gene are common, consistent with Pten-knockout mice developing T-ALL. To better understand T-ALL pathogenesis and identify new therapeutic targets in T-ALL, we developed a Pten-knockout T-ALL mouse model and the mice developed T-ALL within 3 months as expected. We profiled the miRs in the Pten-deficient mouse T-ALL. A576, A577, A578 and A579 are PTEN-knockout mouse T-ALL samples. A580 andA 581 are wild-type mouse thymocytes.
2016-08-25 | E-MTAB-5053 | biostudies-arrayexpress
Project description:Gene expression of hepatocyt-specific knockout of Pten and of Pten and Tgfbr2 in mice as a model for human cholangiocarcinoma was determined Affymetrix Mouse 1.0ST chips were used to measure gene expression Gene expression of the following mouse livers were characterized A. WT (n=3). B. Pten-/- (n=4). C. Pten-/- Tgfbr2-/- (n=4).
2016-02-26 | E-GEOD-66717 | biostudies-arrayexpress
Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).
2012-07-19 | E-GEOD-38008 | biostudies-arrayexpress
Project description:PTEN encodes a tumor suppressor with lipid and protein phosphatase activities whose dysfunction has been implicated in melanomagenesis; less is known about how its phosphatases regulate melanoma metastasis. We show that PTEN expression negatively correlates with metastatic progression in human melanoma samples and a PTEN-deficient mouse melanoma model. Wildtype PTEN expression inhibited melanoma cell invasiveness and metastasis in a dose-dependent manner, behaviors that specifically required PTEN protein phosphatase activity. PTEN phosphatase activity regulated metastasis through Entpd5. Entpd5 knockdown reduced metastasis and IGF1R levels while promoting ER stress. In contrast, Entpd5 overexpression promoted metastasis and enhanced IGF1R levels, while reducing ER stress. Moreover, Entpd5 expression was regulated by the ER stress sensor ATF6. Altogether, our data show that PTEN phosphatase activity inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6, thereby identifying novel candidate therapeutic targets for the treatmtreatingwith PTEN mutant melanoma.
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Project description:The PTEN:P-Rex2 complex is a commonly mutated signaling nodes in metastatic cancer. The dual-specificity phosphatase PTEN canonically functions as a tumour suppressor by hydrolysing PI(3,4,5)P3 to PI(4,5)P2 to inhibit PI3K-AKT signaling. P-Rex2 is a RhoGTPase guanine nucleotide exchange factor activated by both Gβγ and PI(3,4,5)P3 downstream of G protein-coupled receptor and receptor tyrosine kinase signaling. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cell proliferation. However, structural insights into both PTEN:P-Rex2 complex assembly and its dysregulation by cancer-associated mutations remain limited. Here, using crosslinking mass spectrometry and functional studies, we provide mechanistic insights into PTEN:P-Rex2 complex assembly and co-inhibition. PTEN is anchored to P-Rex2 by interactions between the PTEN C-terminal tail PDZ-interacting motif and the second PDZ domain of P-Rex2. This interaction bridges PTEN across the P-Rex2 surface, occluding PI(3,4,5)P3 hydrolysis. Conversely, PTEN both allosterically promotes an autoinhibited P-Rex2 conformation and occludes Gβγ binding. These insights allow us to define a new gain-of-function class of cancer mutations within the PTEN:P-Rex2 interface that uncouples PTEN inhibition of Rac1 signaling. In addition, we observe synergy between PTEN deactivating and P-Rex2 truncation mutations that combine to drive Rac1 activation to a greater extent than either single mutation alone.
2022-08-12 | PXD021126 | Pride
Project description:The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. Whilst the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Using knock-in (KI) mice harbouring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. The dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN-loss driven cancers.
2020-10-16 | GSE140289 | GEO
Project description:Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling for MEF cells from a Ptenhy/+ mouse model. We have analyzed the survival and tumor spectrum in a population of Pten âhypermorphicâ mice (Ptenhy/+), which express approximately 80% of total Pten protein. Notably, the Ptenhy/+ developed a spectrum of tumors of variable latencies, with breast tumors occurring at the highest penetrance. Surprisingly, all breast tumors analyzed retain two intact copies of Pten, and maintain Pten protein levels above that observed in heterozygosity. Importantly, subtle down-regulation of Pten was found to alter the expression profile of genes involved in cell proliferation. Taken together, our findings support the notion that initiation of tumorigenesis can occur in the absence of genetic hits, thereby questioning the uniqueness of a saltatory model for cancer susceptibility. In order to understand whether subtle variations in Pten level may affect pathways involved in tumorigenesis, we analyzed the genome-wide expression profile of Ptenhy/+ mouse embryonic fibroblasts (MEFs). In the Ptenhy/+ mouse model, mice are born with approximately 80% of total Pten protein and are viable and normally fertile. To decrease the expression level of Pten below homozygosity, we targeted intron 3 of Pten with a neomycin (Neo) cassette, under the control of the strong CMV promoter, thereby taking advantage of transcriptional interference. Next, we intercrossed Pten hy/+ mice with Pten+/- mice to generate cohorts of hypomorphic littermate mice with decreasing levels of Pten expression as follows: Ptenwt > Ptenhy/+ > Pten+/- >Ptenhy/- mice littermates. To preserve a constant 129/C57BL/6 mixed genetic background, we have crossed Pten hy/+ mice with Pten +/- for more than seven generations prior to analysis. As expected, Ptenhy/+ mouse embryonic fibroblasts (MEFs) display a level of Pten protein below Ptenwt and above Pten+/- .
2010-02-21 | E-GEOD-20316 | biostudies-arrayexpress