Regulation of Bim in Health and Disease

Sionov, Ronit Vogt; Vlahopoulos, Spiros; Granot, Zvi

doi:10.18632/oncotarget.5492

Cited by 164 publications

(133 citation statements)

References 651 publications

(1,186 reference statements)

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“…86 BIM contains a single BCL2 homology-3 domain and interacts with all anti-apoptotic proteins of the BCL2 superfamily, making it an efficient killer that promotes apoptosis. 87 In PDAC, BIM expression is significantly reduced by the direct regulation of miR-24 and its restoration by miR-24 inhibition promotes apoptosis and inhibits cell cycle. 88 TRANSCRIPTION FACTORS AND DNA METHYLATION Genes, other than those discussed above, interact with miRNAs in PDAC.…”

Section: Apoptosismentioning

confidence: 99%

MicroRNA in pancreatic cancer

2016

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Patients with PDAC are often asymptomatic, and many have lymph node and distant metastases as well as vessel invasion upon diagnosis. Surgery and current chemotherapy have limited efficacy for improving prognosis, which accounts for overall median survival of 8.6 months and a 9.7% 5-year survival rate. MicroRNAs (miRNAs) are attracting increasing attention because of their association with tumour progression. At least 50% of miRNAs that are aberrantly expressed in tumours have important roles as post-transcriptional regulators and exhibit oncogenic or tumour suppressive activities by directly binding to their target messenger RNAs. Various techniques are available to identify miRNAs that are differentially expressed in cancerous vs normal tissues. In this review, we summarise the miRNA profiles of normal pancreatic tissue and cancer tissue of patients with PDACs and characterise the expression of miRNAs associated with tumour progression. Further, we highlight the target genes and signalling pathways of miRNAs that are aberrantly expressed in PDACs. This knowledge may lead to the development of preventive and therapeutic strategies for treating this deadly disease.

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Section: Apoptosismentioning

confidence: 99%

MicroRNA in pancreatic cancer

2016

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“…Interestingly, the mir-35 family of miRNA genes is found only in other nematodes, although miRNAs with homologous functions might very well exist in higher animals, such as those reported to repress the mammalian BH3-only gene Bim (for review, see Sionov et al 2015). However, the miR-58 family of miRNAs is homologous in both sequence and function to the bantam miRNA in Drosophila, which controls the expression of the proapoptotic gene hid (Brennecke et al 2003).…”

Section: Conservation Of Mirna-dependent Control Of Programmed Cell Dmentioning

confidence: 99%

“…Mammalian BH3-only genes are also subject to post-transcriptional regulation via microRNAs (miRNAs). It has been demonstrated, for example, that the 3 ′ untranslated region (UTR) of Bim mRNA is the target of several miRNAs, which act to down-regulate and fine-tune Bim expression (Ventura et al 2008;Kole et al 2011;Qian et al 2011;Pernaute et al 2014; for review, see Sionov et al 2015).…”

mentioning

confidence: 99%

miRNAs cooperate in apoptosis regulation during C. elegans development

et al. 2017

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Programmed cell death occurs in a highly reproducible manner during Caenorhabditis elegans development. We demonstrate that, during embryogenesis, miR-35 and miR-58 bantam family microRNAs (miRNAs) cooperate to prevent the precocious death of mothers of cells programmed to die by repressing the gene egl-1, which encodes a proapoptotic BH3-only protein. In addition, we present evidence that repression of egl-1 is dependent on binding sites for miR-35 and miR-58 family miRNAs within the egl-1 3 ′ untranslated region (UTR), which affect both mRNA copy number and translation. Furthermore, using single-molecule RNA fluorescent in situ hybridization (smRNA FISH), we show that egl-1 is transcribed in the mother of a cell programmed to die and that miR-35 and miR-58 family miRNAs prevent this mother from dying by keeping the copy number of egl-1 mRNA below a critical threshold. Finally, miR-35 and miR-58 family miRNAs can also dampen the transcriptional boost of egl-1 that occurs specifically in a daughter cell that is programmed to die. We propose that miRNAs compensate for lineagespecific differences in egl-1 transcriptional activation, thus ensuring that EGL-1 activity reaches the threshold necessary to trigger death only in daughter cells that are programmed to die.

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“…Thus, in addition to Akt, Erk and IKK have been shown to inhibit Foxo3 activity, and various pathways are known to counter Foxo3 inhibition (35). In addition, Bim is regulated by Foxo3-independent transcriptional, posttranscriptional, and posttranslational mechanisms (36), which could differ depending on the strength/duration of TCR signaling, costimulation, and inflammation.…”

Section: Generation Of Protective Long-lasting Cd8mentioning

confidence: 99%

Akt signaling is critical for memory CD8 ⁺ T-cell development and tumor immune surveillance

Rogel

Willoughby

Buchan

et al. 2017

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

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Memory CD8+ T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8+ T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8+ T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored. Using CD8+ T cells from pdk1K465E/K465E knockin mice, we found that decreased Akt activity inhibited the survival of T cells during the effector-to-memory cell transition and abolished their differentiation into C-X-C chemokine receptor 3 (CXCR3)loCD43lo effector-like memory cells. Consequently, antitumor immunity by CD8+ T cells that display defective Akt signaling was substantially diminished during the memory phase. Reduced memory T-cell survival and altered memory cell differentiation were associated with up-regulation of the proapoptotic protein Bim and the T-box transcription factor eomesodermin, respectively. These findings suggest an important role for effector-like memory CD8+ T cells in tumor immune surveillance and identify Akt as a key signaling node in the development of protective memory CD8+ T-cell responses.

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Regulation of Bim in Health and Disease

Cited by 164 publications

References 651 publications

MicroRNA in pancreatic cancer

MicroRNA in pancreatic cancer

miRNAs cooperate in apoptosis regulation during C. elegans development

Akt signaling is critical for memory CD8 ⁺ T-cell development and tumor immune surveillance

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Regulation of Bim in Health and Disease

Cited by 164 publications

References 651 publications

MicroRNA in pancreatic cancer

MicroRNA in pancreatic cancer

miRNAs cooperate in apoptosis regulation during C. elegans development

Akt signaling is critical for memory CD8 + T-cell development and tumor immune surveillance

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Akt signaling is critical for memory CD8 ⁺ T-cell development and tumor immune surveillance