scholarly journals Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology

2016 ◽  
Vol 23 (5) ◽  
pp. 377-390 ◽  
Author(s):  
Jaesung (Peter) Choi ◽  
Yu Zheng ◽  
David J Handelsman ◽  
Ulla Simanainen
Keyword(s):  
Estrogen Receptor Alpha ◽  
Uterine Cancer ◽  
Intraepithelial Neoplasia ◽  
Glandular Epithelium ◽  
Wild Type ◽  
Double Knockout ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion ◽  
Uterine Growth

Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice. The double knockout restricted to glandular epithelium showed that AR inactivation enhanced PTEN deletion-induced uterine pathology with development of intraepithelial neoplasia by 20 weeks of age. In ugePTENARKO, 6/10 (60%) developed intraepithelial neoplasia, whereas 3/10 (30%) developed only glandular hyperplasia in ugePTENKO uterus. No uterine pathology was observed in WT (n=8) and ugeARKO (n=7) uteri. Uterine weight was significantly (P=0.002) increased in ugePTENARKO (374±97 mg (mean±s.e.)) compared with WT (97±6 mg), ugeARKO (94±12 mg), and ugePTENKO (205±33 mg). Estrogen receptor alpha (ERα) and P-AKT expression was modified by uterine pathology but did not differ between ugePTENKO and ugePTENARKO, suggesting that its expressions are not directly affected by androgens. However, progesterone receptor (PR) expression was reduced in ugePTENARKO compared to ugePTENKO uterus, suggesting that PR expression could be regulated by glandular epithelial AR inactivation. In conclusion, glandular epithelial AR inactivation (with persistent stromal AR action) enhanced PTEN deletion-induced uterine pathology possibly by downregulating PR expression in the uterus.

scholarly journals Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer

2015 ◽  
Vol 22 (5) ◽  
pp. 687-701 ◽  
Author(s):  
Jaesung (Peter) Choi ◽  
Reena Desai ◽  
Yu Zheng ◽  
Mu Yao ◽  
Qihan Dong ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Uterine Cancer ◽  
Serum Testosterone ◽  
Cowden Syndrome ◽  
Corpora Lutea ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Uterine Growth ◽  
Uterine Cancers ◽  
Reproductive Cancers

Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

Regulation of Phosphoinositide Metabolism, Akt Phosphorylation, and Glucose Transport by PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome 10) in 3T3-L1 Adipocytes

2001 ◽  
Vol 15 (8) ◽  
pp. 1411-1422 ◽  
Author(s):  
Hiraku Ono ◽  
Hideki Katagiri ◽  
Makoto Funaki ◽  
Motonobu Anai ◽  
Kouichi Inukai ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Dominant Negative ◽  
Phosphoinositide Metabolism ◽  
Transport Activity ◽  
Wild Type ◽  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Akt Phosphorylation ◽  
Tensin Homolog ◽  
Phosphorylation Level

Abstract To investigate the roles of PTEN (phosphatase and tensin homolog deleted on chromosome 10) in the regulation of 3-position phosphorylated phosphoinositide metabolism as well as insulin-induced Akt phosphorylation and glucose metabolism, wild-type PTEN and its phosphatase-dead mutant (C124S) with or without an N-terminal myristoylation tag were overexpressed in Sf-9 cells and 3T3-L1 adipocytes using baculovirus and adenovirus systems, respectively. When expressed in Sf-9 cells together with the p110α catalytic subunit of phosphoinositide 3-kinase, myristoylated PTEN markedly reduced the accumulations of both phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate induced by p110α. In contrast, overexpression of the C124S mutants apparently increased these accumulations. In 3T3-L1 adipocytes, insulin-induced accumulations of phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate were markedly suppressed by overexpression of wild-type PTEN with the N-terminal myristoylation tag, but not by that without the tag. On the contrary, the C124S mutants of PTEN enhanced insulin-induced accumulations of phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Interestingly, the phosphorylation level of Akt at Thr308 (Akt2 at Thr309), but not at Ser473 (Akt2 at Ser474), was revealed to correlate well with the accumulation of phosphatidylinositol 3,4,5-trisphosphate modified by overexpression of these PTEN proteins. Finally, insulin-induced increases in glucose transport activity were significantly inhibited by the overexpression of myristoylated wild-type PTEN, but were not enhanced by expression of the C124S mutant of PTEN. Therefore, in conclusion, 1) PTEN dephosphorylates both phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate in vivo, and the C124S mutants interrupt endogenous PTEN activity in a dominant-negative manner. 2) The membrane targeting process of PTEN may be important for exerting its function. 3) Phosphorylations of Thr309 and Ser474 of Akt2 are regulated differently, and the former is regulated very sensitively by the function of PTEN. 4) The phosphorylation level of Ser474, but not that of Thr309, in Akt2 correlates well with insulin-stimulated glucose transport activity in 3T3-L1 adipocytes. 5) The activity of endogenous PTEN may not play a major role in the regulation of glucose transport activity in 3T3-L1 adipocytes.

scholarly journals PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Jorge A. Benitez ◽  
Jianhui Ma ◽  
Matteo D’Antonio ◽  
Antonia Boyer ◽  
Maria Fernanda Camargo ◽  
...  
Keyword(s):  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Growth Defect ◽  
Tumour Suppressor Genes ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion ◽  
Therapeutic Opportunity ◽  
Associated Function

Abstract Glioblastoma (GBM) is the most lethal type of human brain cancer, where deletions and mutations in the tumour suppressor gene PTEN (phosphatase and tensin homolog) are frequent events and are associated with therapeutic resistance. Herein, we report a novel chromatin-associated function of PTEN in complex with the histone chaperone DAXX and the histone variant H3.3. We show that PTEN interacts with DAXX and, in turn PTEN directly regulates oncogene expression by modulating DAXX-H3.3 association on the chromatin, independently of PTEN enzymatic activity. Furthermore, DAXX inhibition specifically suppresses tumour growth and improves the survival of orthotopically engrafted mice implanted with human PTEN-deficient glioma samples, associated with global H3.3 genomic distribution changes leading to upregulation of tumour suppressor genes and downregulation of oncogenes. Moreover, DAXX expression anti-correlates with PTEN expression in GBM patient samples. Since loss of chromosome 10 and PTEN are common events in cancer, this synthetic growth defect mediated by DAXX suppression represents a therapeutic opportunity to inhibit tumorigenesis specifically in the context of PTEN deletion.

scholarly journals Intestinal epithelial-specific PTEN inactivation results in tumor formation

2011 ◽  
Vol 301 (5) ◽  
pp. G856-G864 ◽  
Author(s):  
Do-Sun Byun ◽  
Naseem Ahmed ◽  
Shannon Nasser ◽  
Joongho Shin ◽  
Sheren Al-Obaidi ◽  
...  
Keyword(s):  
Cell Fate ◽  
Intestinal Epithelium ◽  
Suppressor Gene ◽  
Major Effect ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of phosphatidylinositol 3-kinase (PI3K) signaling that is frequently inactivated in colorectal cancer through mutation, loss of heterozygosity, or epigenetic mechanisms. The aim of this study was to determine the effect of intestinal-specific PTEN inactivation on intestinal epithelial homeostasis and tumorigenesis. PTEN was deleted specifically in the intestinal epithelium, by crossing PTEN Lox/ Lox mice with villin Cre mice. PTEN was robustly expressed in the intestinal epithelium and maximally in the differentiated cell compartment. Targeted inactivation of PTEN in the intestinal epithelium of PTEN Lox/ Lox/villin Cre mice was confirmed by genotyping, immunohistochemistry, and qPCR. While intestinal-specific PTEN deletion did not have a major effect on cell fate determination or proliferation in the small intestine, it did increase phosphorylated (p) protein kinase B (AKT) expression in the intestinal epithelium, and 19% of animals developed small intestinal adenomas and adenocarcinomas at 12 mo of age. These tumors demonstrated pAKT and nuclear β-catenin staining, indicating simultaneous activation of the PI3K/AKT and Wnt signaling pathways. These findings demonstrate that, while PTEN inactivation alone has a minimal effect on intestinal homeostasis, it can facilitate tumor promotion upon deregulation of β-catenin/TCF signaling, further establishing PTEN as a bona fide tumor suppressor gene in intestinal cancer.

scholarly journals Screening for germline phosphatase and tensin homolog-mutations in suspected Cowden syndrome and Cowden syndrome-like families among uterine cancer patients

2015 ◽  
Vol 9 (4) ◽  
pp. 1782-1786 ◽  
Author(s):  
GERASIMOS TZORTZATOS ◽  
CHRISTOS ARAVIDIS ◽  
ANNIKA LINDBLOM ◽  
MIRIAM MINTS ◽  
EMMA THAM
Keyword(s):  
Cancer Patients ◽  
Uterine Cancer ◽  
Cowden Syndrome ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

scholarly journals Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals

2015 ◽  
Vol 112 (43) ◽  
pp. 13342-13347 ◽  
Author(s):  
Helen He Zhu ◽  
Xiaolin Luo ◽  
Kaiqing Zhang ◽  
Jian Cui ◽  
Huifang Zhao ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Myeloproliferative Neoplasm ◽  
Positive Function ◽  
Double Knockout ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Negative Role ◽  
Cell Type Specific ◽  
Deficient Mice

Previous data suggested a negative role of phosphatase and tensin homolog (Pten) and a positive function of SH2-containing tyrosine phosphatase (Shp2)/Ptpn11 in myelopoiesis and leukemogenesis. Herein we demonstrate that ablating Shp2 indeed suppressed the myeloproliferative effect of Pten loss, indicating directly opposing functions between pathways regulated by these two enzymes. Surprisingly, the Shp2 and Pten double-knockout mice suffered lethal anemia, a phenotype that reveals previously unappreciated cooperative roles of Pten and Shp2 in erythropoiesis. The lethal anemia was caused collectively by skewed progenitor differentiation and shortened erythrocyte lifespan. Consistently, treatment of Pten-deficient mice with a specific Shp2 inhibitor suppressed myeloproliferative neoplasm while causing anemia. These results identify concerted actions of Pten and Shp2 in promoting erythropoiesis, while acting antagonistically in myeloproliferative neoplasm development. This study illustrates cell type-specific signal cross-talk in blood cell lineages, and will guide better design of pharmaceuticals for leukemia and other types of cancer in the era of precision medicine.

The association of Phosphatase and tensin homolog (PTEN) deletion and prostate cancer risk: A meta-analysis

2016 ◽  
Vol 83 ◽  
pp. 114-121 ◽  
Author(s):  
Tianyi Gao ◽  
Yanping Mei ◽  
Huiling Sun ◽  
Zhenlin Nie ◽  
Xiangxiang Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Meta Analysis ◽  
Prostate Cancer Risk ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion

scholarly journals Association between decreased expression of estrogen receptor alpha, androgen receptor and phosphatase and tensin homolog immunoexpression in the canine prostate

2019 ◽  
Vol 39 (1) ◽  
pp. 40-46
Author(s):  
Priscila E. Kobayashi ◽  
Marcela M.P. Rodrigues ◽  
Fatima Gartner ◽  
Alexandra Rema ◽  
Carlos E. Fonseca-Alves ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Estrogen Receptor ◽  
Androgen Receptor ◽  
Hormonal Therapy ◽  
Estrogen Receptor Alpha ◽  
Prostate Gland ◽  
Basal Cells ◽  
Phosphatase And Tensin Homolog ◽  
Receptor Alpha ◽  
Tensin Homolog

ABSTRACT: Canine prostate gland is a hormonal dependent organ and its imbalance of estrogen and androgen receptor expressions are directly associated with the development of different diseases. Due to the lack of information regarding the behavior of the aforementioned receptors in canine prostate cancer (PC), this study aimed to identify estrogen receptor alpha (ERα), androgen receptor (AR), Ki67 and phosphatase and tensin homolog (PTEN) protein expressions in canine PC by immunohistochemistry. We found nuclear expression of ERα and AR in the epithelial cells of normal canine samples and a loss of protein expression in PC samples. Normal samples showed Ki67 expression in a few basal cells and the PC samples showed the highest mean of positive cells (253.1). Canine prostate cancer showed a high proliferative index, which was associated with independence of hormonal actuation. PTEN showed positive nuclear and cytoplasmic expression in normal canine samples and a loss in PC. Loss of ERα, AR and PTEN indicated that canine PC exhibits the same immunohistochemical phenotype as in human patients with PC resistant to hormonal therapy. Therefore, canine PC should be considered as a model to study human PC resistant to hormonal therapy.

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