scholarly journals Unrestrained Mammalian Target of Rapamycin Complexes 1 and 2 Increase Expression of Phosphatase and Tensin Homolog Deleted on Chromosome 10 to Regulate Phosphorylation of Akt Kinase

2011 ◽  
Vol 287 (6) ◽  
pp. 3808-3822 ◽  
Author(s):  
Falguni Das ◽  
Nandini Ghosh-Choudhury ◽  
Nirmalya Dey ◽  
Chandi Charan Mandal ◽  
Lenin Mahimainathan ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Chromosome 10 ◽  
Akt Kinase ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

scholarly journals Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4560-4568 ◽  
Author(s):  
Bao Hoang ◽  
Patrick Frost ◽  
Yijiang Shi ◽  
Eileen Belanger ◽  
Angelica Benavides ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Kinase Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Phosphatase And Tensin Homolog ◽  
Akt Phosphorylation ◽  
Tensin Homolog ◽  
Complex Protein ◽  
Preclinical Work

Although preclinical work with rapalogs suggests potential in treatment of multiple myeloma (MM), they have been less successful clinically. These drugs allostearically inhibit the mammalian target of rapamycin kinase primarily curtailing activity of the target of rapamycin complex (TORC)1. To assess if the mammalian target of rapamycin within the TORC2 complex could be a better target in MM, we tested a new agent, pp242, which prevents activation of TORC2 as well as TORC1. Although comparable to rapamycin against phosphorylation of the TORC1 substrates p70S6kinase and 4E-BP-1, pp242 could also inhibit phosphorylation of AKT on serine 473, a TORC2 substrate, while rapamycin was ineffective. pp242 was also more effective than rapamycin in achieving cytoreduction and apoptosis in MM cells. In addition, pp242 was an effective agent against primary MM cells in vitro and growth of 8226 cells in mice. Knockdown of the TORC2 complex protein, rictor, was deleterious to MM cells further supporting TORC2 as the critical target for pp242. TORC2 activation was frequently identified in primary specimens by immunostaining for AKT phosphorylation on serine 473. Potential mechanisms of up-regulated TORC2 activity in MM were stimulation with interleukin-6 or insulin-like growth factor 1, and phosphatase and tensin homolog or RAS alterations. Combining pp242 with bortezomib led to synergistic anti-MM effects. These results support TORC2 as a therapeutic target in MM.

scholarly journals Cellular homeostasis, implantation window and unexplained infertility: role of phosphatase and tensin homolog deleted on chromosome 10

2019 ◽  
Vol 8 (7) ◽  
pp. 2754
Author(s):  
Annu Makker ◽  
Madhu Mati Goel ◽  
Kumari Manu ◽  
Renu Makker
Keyword(s):  
Cell Proliferation ◽  
Unexplained Infertility ◽  
Endometrial Cell ◽  
Chromosome 10 ◽  
Cellular Homeostasis ◽  
Phosphatase And Tensin Homolog ◽  
Implantation Window ◽  
Tensin Homolog ◽  
Proliferation And Apoptosis

Background: Balance between endometrial cell proliferation and apoptosis is crucial for successful embryo implantation. PTEN (phosphatase and tensin homolog deleted on chromosome 10), a pro-apoptotic factor, is proposed to be one of the signaling proteins through which estrogen and progesterone act to affect cellular homeostasis. Although reports in literature have suggested role of PTEN in regulating endometrial cell proliferation and apoptosis during window of implantation, its involvement in women with unexplained infertility is not clear. In the present study, we examined expression, cellular distribution and activation status of PTEN, cell proliferation, and apoptosis in midsecretory endometrium from women with unexplained infertility as compared to fertile controls.Methods: Endometrial biopsies from infertile (n=11) and fertile women (n=22) were used for immunohistochemical evaluation of PTEN, phospho-PTEN and Ki67. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay was performed for detection of apoptotic cells.Results: Biopsies from infertile women as compared to fertile controls demonstrated statistically significant: i) decrease in nuclear PTEN (P < 0.001), increase in nuclear phospho-PTEN (P < 0.05), increase in nuclear and cytoplasmic phospho-PTEN/PTEN ratio (P < 0.001 and P < 0.05 respectively) in endometrial stroma, ii) increase in cytoplasmic phospho-PTEN (P < 0.001) and phospho-PTEN/PTEN ratio (P < 0.05) in glandular epithelium (GE), iii) increase in Ki67 labeling in GE (P < 0.01) and stroma (P < 0.05) and, iv) decrease in (P < 0.001) apoptosis.Conclusions: Altered PTEN expression and associated modulation in cellular homeostasis during the implantation window might contribute to mechanism underlying unexplained infertility.

Oncophenotypic Review and Clinical Correlates of Phosphatase and Tensin Homolog on Chromosome 10 Hamartoma Tumor Syndrome

2010 ◽  
Vol 28 (36) ◽  
pp. e767-e768 ◽  
Author(s):  
Mrinal M. Patnaik ◽  
Sania S. Raza ◽  
Sherezade Khambatta ◽  
Peter P. Stanich ◽  
Matthew P. Goetz
Keyword(s):  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Clinical Correlates ◽  
Tensin Homolog

scholarly journals Contribution of mTOR and PTEN to Radioresistance in Sporadic and NF2-Associated Vestibular Schwannomas: A Microarray and Pathway Analysis

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 177 ◽  
Author(s):  
Isabel Gugel ◽  
Florian H. Ebner ◽  
Florian Grimm ◽  
Stefan Czemmel ◽  
Frank Paulsen ◽  
...  
Keyword(s):  
Pathway Analysis ◽  
Radiation Treatment ◽  
Mammalian Target Of Rapamycin ◽  
Neurofibromatosis Type ◽  
P Value ◽  
Mtor Inhibition ◽  
Phosphatase And Tensin Homolog ◽  
Molecular Alterations ◽  
Tensin Homolog ◽  
Systemic Treatments

The use of radiation treatment has increased for both sporadic and neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS). However, there are a subset of radioresistant tumors and systemic treatments that are seldom used in these patients. We investigated molecular alterations after radiation in three NF2-associated and five sporadically operated recurrent VS after primary irradiation. We compared these findings with 49 non-irradiated (36 sporadic and 13 NF2-associated) VS through gene-expression profiling and pathway analysis. Furthermore, we stained the key molecules of the distinct pathway by immunohistochemistry. A total of 195 differentially expressed genes in sporadic and NF2-related comparisons showed significant differences based on the criteria of p value < 0.05 and a two-fold change. These genes were involved in pathways that are known to be altered upon irradiation (e.g., mammalian target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF) signaling). We observed a combined downregulation of PTEN signaling and an upregulation of mTOR signaling in progressive NF2-associated VS after irradiation. Immunostainings with mTOR and PTEN antibodies confirmed the respective molecular alterations. Taken together, mTOR inhibition might be a promising therapeutic strategy in NF2-associated VS progress after irradiation.

scholarly journals PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 719
Author(s):  
Nicola Fusco ◽  
Elham Sajjadi ◽  
Konstantinos Venetis ◽  
Gabriella Gaudioso ◽  
Gianluca Lopez ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Genetic Alterations ◽  
Phosphatase And Tensin Homolog ◽  
Cancer Management ◽  
Tensin Homolog ◽  
Current State ◽  
Tumor Immune Microenvironment ◽  
Damage Response ◽  
Phosphoinositide 3 Kinase

Alterations in the tumor suppressor phosphatase and tensin homolog (PTEN) occur in a substantial proportion of solid tumors. These events drive tumorigenesis and tumor progression. Given its central role as a downregulator of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, PTEN is deeply involved in cell growth, proliferation, and survival. This gene is also implicated in the modulation of the DNA damage response and in tumor immune microenvironment modeling. Despite the actionability of PTEN alterations, their role as biomarkers remains controversial in clinical practice. To date, there is still a substantial lack of validated guidelines and/or recommendations for PTEN testing. Here, we provide an update on the current state of knowledge on biologic and genetic alterations of PTEN across the most frequent solid tumors, as well as on their actual and/or possible clinical applications. We focus on possible tailored schemes for cancer patients’ clinical management, including risk assessment, diagnosis, prognostication, and treatment.

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