Bcl-2 inhibition of T-cell proliferation is related to prolonged T-cell survival

Cheng, Ningli; Janumyan, Yelena; Didion, Lisa; Hofwegen, Chris Van; Yang, Elizabeth; Knudson, C. Michael

doi:10.1038/sj.onc.1207478

Cited by 50 publications

(60 citation statements)

References 40 publications

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“…Importantly, the Bcl-2 high phenotype is highly correlative with both enhanced rate of survival and mitogen responsiveness of T cells, regardless of their differentiation stage. Numerous studies have shown that Bcl-2 has antiapoptotic effects; however, high levels of Bcl-2 also correlated with decreased proliferation, when using Bcl-2 overexpressing transgenic mice (36). In this study, we observed that actively dividing cells expressed high amounts of the Bcl-2 protein (Fig.…”

Section: Discussionsupporting

confidence: 52%

Distinct Mechanisms Control Human Naive and Antigen-Experienced CD8+ T Lymphocyte Proliferation

Migliaccio

Alves

Romero

et al. 2006

The Journal of Immunology

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Human Ag-specific CD8+ T lymphocytes are heterogeneous and include functionally distinct populations. In this study, we report that at least two distinct mechanisms control the expansion of circulating naive, memory, and effector CD8+ T lymphocytes when exposed to mitogen or Ag stimulation. The first one leads to apoptosis and occurs shortly after in vitro stimulation. Susceptibility to cell death is prominent among primed T cell subsets, and it is inversely correlated with the size of the ex vivo Bcl-2high population within these subsets. Importantly, the Bcl-2high phenotype is associated to the proportion of responsive CD8+ T cells, independently of their differentiation stage. The second one depends on the expression of newly synthesized cyclin-dependent kinase inhibitor p16INK4a that occurs in a significant fraction of T cells that had been actively cycling, leading to their cell cycle arrest upon stimulation. Strikingly, accumulation of p16INK4a protein preferentially occurs in naive as opposed to primed derived T lymphocytes and is not related to apoptosis. Significant levels of p16 are readily detectable in a small number of ex vivo CD8+ T cells. Our observations reveal that activation-induced p16 expression represents an alternative process to apoptosis, limiting the proliferation potential of activated naive derived T lymphocytes.

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Section: Discussionsupporting

confidence: 52%

Distinct Mechanisms Control Human Naive and Antigen-Experienced CD8+ T Lymphocyte Proliferation

Migliaccio

Alves

Romero

et al. 2006

The Journal of Immunology

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“…In mouse, forced expression of Bcl-2 delays activation-induced T cells (22,23), whereas Bcl-2 deficiency hastens (22) cell-cycle entry of T cells. The antiproliferative action of Bcl-2 is believed to act by elevating the expression of the negative cell-cycle regulator p27 and retarding S-phase entry (24,25).…”

Section: Discussionmentioning

confidence: 99%

Sperm-borne microRNA-34c is required for the first cleavage division in mouse

Liu

Pang

Chiu

et al. 2011

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

386

335

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In mammals, the sperm deliver mRNA of unknown function into the oocytes during fertilization. The role of sperm microRNAs (miRNAs) in preimplantation development is unknown. miRNA profiling identified six miRNAs expressed in the sperm and the zygotes but not in the oocytes or preimplantation embryos. Sperm contained both the precursor and the mature form of one of these miRNAs, miR-34c. The absence of an increased level of miR-34c in zygotes derived from α-amanitin-treated oocytes and in parthenogenetic oocytes supported a sperm origin of zygotic miR-34c. Injection of miR-34c inhibitor into zygotes inhibited DNA synthesis and significantly suppressed first cleavage division. A 3′ UTR luciferase assay and Western blotting demonstrated that miR-34c regulates B-cell leukemia/lymphoma 2 (Bcl-2) expression in the zygotes. Coinjection of anti-Bcl-2 antibody in zygotes partially reversed but injection of Bcl-2 protein mimicked the effect of miR-34c inhibition. Oocyte activation is essential for the miR-34c action in zygotes, as demonstrated by a decrease in 3′ UTR luciferase reporter activity and Bcl-2 expression after injection of precursor miR-34c into parthenogenetic oocytes. Our findings provide evidence that sperm-borne miR-34c is important for the first cell division via modulation of Bcl-2 expression.

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“…Due to shared protein functions in apoptosis and proliferation of BCL-2 family proteins is seems that the function in the liver is likely to be related to compensatory proliferation. 22,23 Previous studies in globally deficient BID mice, or in mice with Bcl-2 overexpression, showed impairment in cell proliferation. 21,24,25 However, global Bid deficiency by itself can lead to an increased incidence of chronic myelomonocytic leukemia in aged mice and similar to this, Bad deficiency has been reported to promote the development of lymphoid tumors either spontaneously or in response to sublethal radiation.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

et al. 2015

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Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion -a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid Δhep ) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid Δhep mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid Δhep animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF-α, IL-1ß, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid Δhep mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid Δhep mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid Δhep and Bid flo/flo mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival.

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Bcl-2 inhibition of T-cell proliferation is related to prolonged T-cell survival

Cited by 50 publications

References 40 publications

Distinct Mechanisms Control Human Naive and Antigen-Experienced CD8+ T Lymphocyte Proliferation

Distinct Mechanisms Control Human Naive and Antigen-Experienced CD8+ T Lymphocyte Proliferation

Sperm-borne microRNA-34c is required for the first cleavage division in mouse

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

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