Cutting Edge: T Cell Requirement for CD28 Costimulation Is Due to Negative Regulation of TCR Signals by PTEN

Buckler, Jodi L.; Walsh, Patrick; Porrett, Paige M.; Choi, Yongwon; Turka, Laurence A.

doi:10.4049/jimmunol.177.7.4262

Cited by 76 publications

(84 citation statements)

References 24 publications

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“…5D). In the control PBS-injected group, 100% of tPTEN Ϫ/Ϫ mice (n ϭ 16) had died by 15 weeks of age as expected (12,34). Forty percent of dexamethasone-treated tPTEN Ϫ/Ϫ mice died Ϸ3-4 weeks later, consistent with the idea that reduction of DP thymocytes for 3 weeks led to some delay in lymphoma development.…”

Section: Transient Reduction Of Dp Thymocytes Within a 3-week Windowsupporting

confidence: 66%

Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice

Xue

Nolla

Suzuki

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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PTEN is a tumor suppressor gene but whether cancer can develop in all PTEN-deficient cells is not known. In T cell-specific PTEN-deficient (tPTEN ؊/؊ ) mice, which suffer from mature T cell lymphomas, we found that premalignancy, as defined by elevated AKT and senescence pathways, starts in immature T cell precursors and surprisingly not in mature T cells. Premalignancy only starts in 6-week-old mice and becomes much stronger in 9-week-old mice although PTEN is lost since birth. tPTEN ؊/؊ immature T cells do not become tumors, and senescence has no role in this model because these cells exist in a novel cell cycle state, expressing proliferating proteins but not proliferating to any significant degree. Instead, the levels of p27 kip1 , which is lower in tPTEN ؊/؊ immature T cells and almost nonexistent in tPTEN ؊/؊ mature T cells, correlate with the proliferation capability of these cells. Interestingly, transient reduction of these cancer precursor cells in adult tPTEN ؊/؊ mice within a crucial time window significantly delayed lymphomas and mouse lethality. Thus, loss of PTEN alone is not sufficient for cells to become cancerous, therefore other developmental events are necessary for tumor formation.lymphomas ͉ senescence ͉ double positive thymocytes ͉ p27 ͉ cyclin A H ow premalignancy arises, how the cells respond to it, and what the molecular steps leading to tumors are remain crucial questions in understanding cancer and designing possible future therapies. It has been widely accepted that cancer can be initiated by a combination of gain-of-function mutations of oncogenes and/or loss-of-function mutations of tumor suppressor genes. Whether cells become transformed immediately or other ''tumorinitiating'' events are still needed for tumor development is not completely known. Recent evidence has demonstrated that leukemia and some solid tumors might contain ''cancer stem cells'' within the tumors (1, 2). This population is distinct from the cancer cells, exhibit the ability to self-renew, and undergo differentiation to produce cancer cells. However, a more recent study strongly argued against the stem cell model for cancer at least for myc-induced B cell lymphomas and ras-induced T cell lymphomas (3). As the development of B and T cells is a sequential process occurring in different organs, one possible explanation in these cases is that the tumorinitiating cells might be located in other organs rather than the tumor-arising sites.PTEN is a negative regulator of PI3 kinase pathway (4, 5) and a tumor suppressor gene commonly lost or inactivated in many human cancers. In addition, germ-line PTEN mutations result in the Cowden syndrome, in which patients develop hyperplastic lesions in multiple organs with increased risks of malignant transformation (6, 7). Thus, understanding PTEN biology and how it regulates cell death and cell proliferation during tumor development should yield significant insights into how cancer cells arise. The importance of PTEN in controlling tumor formation was also shown by the phenoty...

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Section: Transient Reduction Of Dp Thymocytes Within a 3-week Windowsupporting

confidence: 66%

Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice

Xue

Nolla

Suzuki

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…This was supported by a previous study, which revealed that PTEN deficiency serves an important function in the oncogenesis of T cell lymphoma (21), and Pten-knockout mice will develop T cell lymphoma uniformly within 10-16 weeks (22)(23)(24)(25). No significant difference in the expression levels of PTEN in the control, tumor and non-tumor groups of the liver, kidney and spleen were identified, indicating that there was no association between PTEN expression level and thymic lymphoma metastasis.…”

Section: Discussionsupporting

confidence: 68%

Analysis of the expression level and methylation of tumor protein p53, phosphatase and tensin homolog and mutS homolog 2 in N-methyl-N-nitrosourea-induced thymic lymphoma in C57BL/6 mice

Huo

Zhang

et al. 2017

Oncology Letters

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Abstract. Tumorigenesis is often caused by somatic mutation or epigenetic changes in genes that regulate aspects of cell death, proliferation and survival. Although the functions of multiple tumor suppressor genes have been well studied in isolation, how these genes cooperate during the progression of a single tumor remains unclear in numerous cases. The present study used N-methyl-N-nitrosourea (MNU), one of the most potent mutagenic nitrosourea compounds, to induce thymic lymphoma in C57BL/6J mice. Subsequently, the protein expression levels of phosphatase and tensin homolog (PTEN), transformation protein 53 and mutS homolog 2 (MSH2) were evaluated concomitantly in the thymus, liver, kidney and spleen of MNU-treated mice by western blotting. To determine whether changes in expression level were due to aberrant epigenetic regulation, the present study further examined the methylation status of each gene by MassARRAY analysis. During the tumorigenesis process of an MNU-induced single thymic lymphoma, the expression level of PTEN was revealed to be reduced in thymic lymphoma samples but not in normal or non-tumor thymus tissue samples. Furthermore, a marked reduction of P53 expression levels were demonstrated in thymic lymphomas and spleens with a metastatic tumor. Conversely, MSH2 upregulation was identified only in liver, kidney, and spleen samples that were infiltrated by thymic lymphoma cells. Furthermore, the present study revealed that a number of 5'-C-phosphate-G-3' sites located in the promoter of aberrantly expressed genes had significantly altered methylation statuses. These results improve the understanding of the course of mutagen-induced cancer, and highlight that epigenetic regulation may serve an important function in cancer.

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“…However, it is difficult to judge from this type of analysis whether PTEN-null T cells traffic normally in the periphery because T cell numbers in secondary lymphoid organs are determined by a balance of the following factors: the efficiency of transendothelial migration from the blood into secondary lymphoid tissue; the homeostatic proliferation of peripheral T cells in the lymphopenic environment found in neonates (Min et al, 2002); and the rate at which cells egress secondary lymphoid tissue (Schwab and Cyster, 2007). In this respect, the enhanced survival and proliferative properties described for PTEN-null peripheral T cells (Suzuki et al, 2001;Buckler et al, 2006) could mask any trafficking problems.…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

Finlay¹,

Sinclair²,

Feijóo³

et al. 2009

J Cell Biol

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Cutting Edge: T Cell Requirement for CD28 Costimulation Is Due to Negative Regulation of TCR Signals by PTEN

Cited by 76 publications

References 24 publications

Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice

Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice

Analysis of the expression level and methylation of tumor protein p53, phosphatase and tensin homolog and mutS homolog 2 in N-methyl-N-nitrosourea-induced thymic lymphoma in C57BL/6 mice

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

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