Impaired Fas Response and Autoimmunity in
            <i>Pten</i>
            <sup>+/−</sup>
            Mice

Cristofano, Antonio Di; Kotsi, P.; Peng, Yufeng; Cordon‐Cardo, Carlos; Elkon, Keith B.; Pandolfi, Pier Paolo

doi:10.1126/science.285.5436.2122

Cited by 487 publications

(385 citation statements)

References 27 publications

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“…PTEN phosphatase antagonizes the activity of PI3K that phosphorylates Akt. It has been demonstrated that Fas-mediated apoptosis is impaired in PTEN-mutant mice, in which phosphorylation of Akt is abnormally elevated [21]. All things considered, our results suggest the possible involvement of PTEN, which increases in expression during terminal follicular development and luteinization, in the regulation of proliferation and differentiation of granulosa cells via regulation of Akt phosphorylation.…”

Section: Discussionsupporting

confidence: 58%

PTEN and Akt expression during growth of human ovarian follicles

Goto

Iwase

Ando

et al. 2007

J Assist Reprod Genet

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Purpose To assess the expression of PTEN and total and phosphorylated Akt in human ovarian follicles during follicular growth. Methods Immunohistochemistry of ovarian tissues and Western blotting and immunofluorescence of primary cultured luteinized granulosa cells for PTEN and Akt. Results Immunoreactivity of Akt was found in the oocytes, granulosa cells and theca cells in primordial follicles, follicles at each growing stage and luteal cells. As the follicles grew, staining for PTEN became intense in the granulosa cells, whereas the intensity of phospho-Akt became weak. Western blotting and immunofluorescence analysis using primary cultured granulosa-lutein cells showed Akt and PTEN expression, and phosphorylation of Akt in vitro. Conclusions PTEN and Akt are present in the granulosa cells during folliculogenesis. An increase in PTEN may lead to changes in proliferation and/or differentiation of granulosa cells during follicular growth via regulation of Akt phosphorylation.

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Section: Discussionsupporting

confidence: 58%

PTEN and Akt expression during growth of human ovarian follicles

Goto

Iwase

Ando

et al. 2007

J Assist Reprod Genet

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“…17 Subsequent studies in animal models have suggested that haploinsufficiency (i.e., loss of a single PTEN allele) alone may be sufficient for inducing protein loss and tumor progression. 32,33 Although definitive studies are lacking in breast cancer, that this may occur in humans is suggested by the fact that heterozygous inactivation of PTEN results in 3 dominantly inherited disorders: Cowden syndrome (associated with a predisposition to thyroid and breast cancers), Bannayan-Zonana syndrome and Lhermitte-Duclos syndrome. [3][4][5] Of course, this more likely suggests that it is easier to mutate the second allele once the first allele is lost.…”

Section: Resultsmentioning

confidence: 99%

PTEN promoter is methylated in a proportion of invasive breast cancers

Khan

Kumagai

Vora

et al. 2004

Intl Journal of Cancer

110

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The PTEN protein is a negative regulator of the Akt pathway, leading to suppression of apoptosis and increased cell survival. Its role as a tumor-suppressor gene has been adequately substantiated, and homozygous mutations have been demonstrated in familial and sporadic cancers. In breast cancers, expression of PTEN protein is lost/reduced in 38% of cases. Somatic mutations are, however, rarely found. Our study was therefore designed to determine if differential methylation of the PTEN promoter region has a role in the transcriptional inactivation of the gene in invasive breast carcinomas. PTEN (MMAC1/TEP1) is a tumor-suppressor gene located on chromosomal subband 10q23.3. 1 It has been implicated in a number of familial and sporadic cancers. 2 Germline mutations have been reported in Cowden syndrome and Bannayan-Zonana syndrome, 2 dominantly inherited conditions causing predisposition to a variety of cancers including breast cancer. 3-5 Homozygous somatic mutations have also been recorded in a high percentage of human tumors, common among which are glioblastoma multiforme 6 -8 and endometrial cancer. 9 -11 Genetic, functional and animal modeling studies have substantiated the tumor-suppressor function of PTEN. The gene encodes a PIP3 phosphatase and regulates negatively the PIP3-Akt pathway, leading to suppression of apoptosis and increased cell survival. [12][13][14][15] PTEN is involved in breast cancers. We have previously demonstrated that expression of PTEN protein is lost/reduced in 38% of invasive breast cancers, a feature that is seen with highest frequency in high-grade carcinomas. 16 Although breast cancers also show 38% LOH at the PTEN locus, 17 somatic mutations have rarely been documented. [17][18][19] Thus, the events leading to loss of protein expression remain unclear. The discrepancy noted in the high incidence of LOH and/or protein loss and low mutation rates points to the possibility of epigenetic mechanisms in the inactivation of PTEN.The importance of epigenetic changes in human cancers is only now being recognized. Of primary interest is aberrant promoter hypermethylation that leads to inappropriate gene silencing. Hypermethylation of a growing number of genes (Rb, p16 INK4a , VHL, E-cadherin, APC and BRCA1, to name a few) occurs in promoter CpG islands in tumor cells and is being revealed as one of the most frequent mechanisms of loss of gene function. 20,21 Epigenetic changes are believed to occur at a higher frequency than genetic changes. The PTEN promoter region has been isolated, 22 and preliminary studies have identified methylation as a mechanism for PTEN inactivation in lung carcinomas. 23 Our study was therefore designed to determine if epigenetic regulation by differential methylation has a role in the transcriptional inactivation of the PTEN gene in invasive breast carcinomas. Normal breast tissue was also tested for methylation of the PTEN promoter and its relationship, if any, to aging. MATERIAL AND METHODSArchived tissue blocks from surgical specimens of 50 patients with in...

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“…While complete deletion of Pten results in embryonic lethality, [16][17][18] Pten +/À mice develop an autoimmune phenotype characterized by lymphadenopathy and splenomegaly that has been attributed to defective B-and T-cell apoptosis. 19 These mice also demonstrated autoimmunity, developing antibodies against nuclear antigens as well as immune complex-mediated glomerular disease. Immunopathology of Pten +/À mice was worsened when both alleles of Pten were deleted in the T-cell compartment.…”

Section: Introductionmentioning

confidence: 99%

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice

et al. 2003

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Phosphatidylinositol 3-kinase (PI3K) has emerged as a critical component of multiple immune system intracellular signalling pathways. The levels and relative ratios of PI3K products, phosphatidylinositol (3,4) bisphosphate (PI(3,4)P 2 ) and phosphatidylinositol (3,4,5) trisphosphate (PIP 3 ), are regulated by inositol phosphatases such as Pten and SHIP. Interestingly, mice heterozygous for Pten, a 3 0 -inositol phosphatase, develop a progressive lymphoproliferative syndrome with autoimmune features. Given the importance of PIP 3 species in regulating immune responses, we hypothesized that heterozygosity for the 5 0 -inositol phosphatase SHIP might exacerbate the autoimmune phenotype of Pten +/À mice. In keeping with this, mice heterozygous for both Pten and SHIP developed lymphoproliferation, hypergammaglobulinaemia, autoantibody titres and renal pathology that were more severe than that of Pten +/À mice. These results suggest that the relative levels of phosphatidylinositol phosphatases are likely critical to immune system homeostasis and they also highlight the potential for gene dosage effects in regulating susceptibility and/or severity of autoimmunity.

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Impaired Fas Response and Autoimmunity in Pten ^+/− Mice

Cited by 487 publications

References 27 publications

PTEN and Akt expression during growth of human ovarian follicles

PTEN and Akt expression during growth of human ovarian follicles

PTEN promoter is methylated in a proportion of invasive breast cancers

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice

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Impaired Fas Response and Autoimmunity in Pten +/− Mice

Cited by 487 publications

References 27 publications

PTEN and Akt expression during growth of human ovarian follicles

PTEN and Akt expression during growth of human ovarian follicles

PTEN promoter is methylated in a proportion of invasive breast cancers

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice

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Impaired Fas Response and Autoimmunity in Pten ^+/− Mice