Discovery and functional characterization of a neomorphic PTEN mutation

Costa, Helio A.; Leitner, Michael G.; Sos, Martin L.; Mavrantoni, Angeliki; Rychkova, Anna; Johnson, Jeffrey R.; Newton, Billy W.; Yee, Muh-Ching; Vega, Francisco; Ford, James M.; Krogan, Nevan J.; Shokat, Kevan M.; Oliver, Dominik; Halaszovich, Christian R.; Bustamante, Carlos D.

doi:10.1073/pnas.1422504112

Cited by 40 publications

(52 citation statements)

References 35 publications

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“…It was predicted by online bioinformatics analysis that miR-17 may be involved in the regulation of PTEN gene expression. Previous results indicated that the PTEN gene is closely related to the proliferation, apoptosis, invasion and metastasis of cells (30). Therefore, it was speculated that the upregulation of miR-17 in AM endometrial cells resulted in the downregulation of PTEN, thus influencing the biological properties of endometrial cells.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-17 downregulates expression of the PTEN gene to promote the occurrence and development of adenomyosis

2017

Experimental and Therapeutic Medicine

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Abstract. The aim of the current study was to evaluate the expression of microRNA (miR)-17 in the endometrial tissues of patients with adenomyosis (AM) and determine its biological function in the occurrence and development of the disease. A total of 45 fresh endometrial tissues of AM patients and 32 normal endometrial tissues were collected from healthy controls. The expression of miR-17 was evaluated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The miR-17-targeting gene phosphatase and tensin homolog (PTEN) was predicted using bioinformatics and its expression was evaluated with RT-qPCR and western blot analysis. Endometrial cells were isolated from patients with AM and healthy controls. They were cultured in vitro and transfected with antagomiR-17 to downregulate miR-17 expression, subsequently cell viability and apoptosis were measured using MTT and flow cytometry. The expression of PTEN and cell cycle-and apoptosis-related proteins were evaluated using western blot analysis. Endometrial cells that stably overexpressed PTEN were screened in vitro by co-culture with G418. A dual-luciferase reporter assay was conducted to verify whether miR-17 was directly bound to PTEN mRNA. The results demonstrated that expression of miR-17 was significantly increased in the endometrial tissues of patients with AM compared with control patients (P<0.05). PTEN mRNA and protein expression were significantly lower in the AM group compared with the control group (P<0.05). When the expression of miR-17 in the cells was downregulated, the expression of PTEN was significantly increased (P<0.05). In addition, expression of Bcl-2 protein was significantly decreased and that of Bax protein significantly increased compared with the negative control (both P<0.05). The expression of cyclins E1 and D1 were also significantly downregulated (P<0.05). When PTEN was overexpressed or miR-17 was downregulated, the viability of endometrial cells significantly decreased and cell apoptosis significantly increased (all P<0.05). A dual-luciferase reporter assay indicated that miR-17 could directly bind to the PTEN mRNA 3'-untranslated region to regulate its expression. Thus the current study indicates that expression of miR-17 was increased in the endometrial tissues of patients with AM and may influence cell apoptosis and cyclin expression through the targeted regulation of PTEN. These results suggest that miR-17 promotes the occurrence and development of AM.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-17 downregulates expression of the PTEN gene to promote the occurrence and development of adenomyosis

2017

Experimental and Therapeutic Medicine

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“…7) and 2 individuals in The PTEN missense variant is within a highly conserved catalytic domain, and it is reported to give rise to completely inactive protein. 26,27 The…”

Section: Pathogenic Variants In Known Crc Susceptibility Genesmentioning

confidence: 99%

Use of multigene‐panel identifies pathogenic variants in several CRC‐predisposing genes in patients previously tested for Lynch Syndrome

et al. 2017

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Background Many families with a high burden of colorectal cancer fulfil the clinical criteria for Lynch Syndrome. However, in about half of these families, no germline mutation in the mismatch repair genes known to be associated with this disease can be identified. The aim of this study was to find the genetic cause for the increased colorectal cancer risk in these unsolved cases. Materials and methods To reach the aim, we designed a gene panel targeting 112 previously known or candidate colorectal cancer susceptibility genes to screen 274 patient samples for mutations. Mutations were validated by Sanger sequencing and, where possible, segregation analysis was performed. Results We identified 73 interesting variants, of whom 17 were pathogenic and 19 were variants of unknown clinical significance in well‐established cancer susceptibility genes. In addition, 37 potentially pathogenic variants in candidate colorectal cancer susceptibility genes were detected. Conclusion In conclusion, we found a promising DNA variant in more than 25 % of the patients, which shows that gene panel testing is a more effective method to identify germline variants in CRC patients compared to a single gene approach.

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“…PTEN loss results in continuous activation of Akt signaling, which is correlated with the shorter overall survival of BRAF V 600E mutated melanoma patients (Bucheit et al, 2014). However, using whole-genome sequencing, Costa et al (2015) identified a novel point mutation (A126G) in the PTEN protein. They found that unlike canonical loss-of-function mutants, A126G mutation could produce an enzymatic gain-of-function in PTEN, activating the Akt signaling pathway and prompting cell proliferation in prostate cancer (Costa et al, 2015).…”

Section: Akt Signaling As a Target Of Tigmentioning

confidence: 99%

“…However, using whole-genome sequencing, Costa et al (2015) identified a novel point mutation (A126G) in the PTEN protein. They found that unlike canonical loss-of-function mutants, A126G mutation could produce an enzymatic gain-of-function in PTEN, activating the Akt signaling pathway and prompting cell proliferation in prostate cancer (Costa et al, 2015). These findings suggest the crucial role of the PTEN mutation in the Akt pathway in cancer.…”

Section: Akt Signaling As a Target Of Tigmentioning

confidence: 99%

The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties

Yan

et al. 2016

Front. Pharmacol.

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Tigecycline (TIG), the first member of glycylcycline bacteriostatic agents, has been approved to treat complicated infections in the clinic because of its expanded-spectrum antibiotic potential. Recently, an increasing number of studies have emphasized the anti-tumor effects of TIG. The inhibitory effects of TIG on cancer depend on several activating signaling pathways and abnormal mitochondrial function in cancer cells. The aim of this review is to summarize the cumulative anti-tumor evidence supporting TIG activity against different cancer types, including acute myeloid leukemia (AML), glioma, non-small cell lung cancer (NSCLC), among others. In addition, the efficacy and side effects of TIG in cancer patients are summarized in detail. Future clinical trials are also to be discussed that will evaluate the security and validate the underlying the tumor-killing properties of TIG.

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Discovery and functional characterization of a neomorphic PTEN mutation

Cited by 40 publications

References 35 publications

MicroRNA-17 downregulates expression of the PTEN gene to promote the occurrence and development of adenomyosis

MicroRNA-17 downregulates expression of the PTEN gene to promote the occurrence and development of adenomyosis

Use of multigene‐panel identifies pathogenic variants in several CRC‐predisposing genes in patients previously tested for Lynch Syndrome

The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties

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