RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry

Jung, Heiyoun; Hsiung, Benjamin; Pestal, Kathleen; Procyk, Emily; Raulet, David H.

doi:10.1084/jem.20120565

Cited by 104 publications

(130 citation statements)

References 47 publications

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“…They are consistent with previous evidence showing that E2F1 transcription factor is responsible for the transcriptional regulation of MICA and PVR in a manner dependent on ROS-induced DDR signaling and p53 independent, and of the mouse NKG2D ligand Rae-1 in response to proliferative signals ( 14,44 ). As far as ULBP1, this kinase affects the protein cellular distribution, but not gene transcription.…”

Section: Discussionsupporting

confidence: 93%

“…p38 MAPK controls MICA and PVR ligand upregulation on drug-treated MM cells through activation of E2F1 transcription factor E2F1 transcription factor is responsible for the transcriptional regulation of NKG2D and DNAM-1 ligand in cells undergoing proliferation or genotoxic stress ( 14,36 ). This transcription factor can be activated in response to different signaling pathway(s), and is stabilized by specific phosphorylation at Ser364, by the Chk2 or p38 kinase ( 37,38 ).…”

Section: Resultsmentioning

confidence: 99%

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p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells

et al. 2016

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The mechanisms that regulate the expression of the NKG2D and DNAM-1 activating ligands are only partially known, but it is now widely established that their expression is finely regulated at transcriptional, post-transcriptional and post-translational level, and involve numerous stress pathways depending on the type of ligand, stressor, and cell context.We show that treatment of Multiple Myeloma (MM) cells with sub-lethal doses of Vincristine (VCR), an anticancer drug that inhibits the assembly of microtubules, stimulates the expression of NKG2D and DNAM-1 activating ligands, rendering these cells more susceptible to NK cell-mediated killing. Herein, we focused our attention on the identification of the signaling pathways leading to de novo surface expression of ULBP-1, and to MICA and PVR upregulation on VCR-treated MM cells, both at protein and mRNA levels.We found that p38MAPK differentially regulates drug-dependent ligand upregulation at transcriptional and post-transcriptional level. More specifically, we observed that ULBP-1 expression is attributable to both increased transcriptional activity mediated by ATM-dependent p53 activation, and enhanced mRNA stability; while the p38-activated E2F1 transcription factor regulates MICA and PVR mRNA expression. All together, our findings reveal a previously unrecognized activity of VCR as anticancer agent, and indicate that in addition to its established ability to arrest cell growth, VCR can also modulate the expression of NKG2D and DNAM-1 activating ligand on tumor cells and thus promoting NK cell-mediated immunosurveillance.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells

et al. 2016

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“…Collectively, these results reveal the importance of E2F1 in the regulation of human NKG2D and DNAM-1 ligands in response to ROS-dependent, drug-induced genotoxic stress and suggest a more general role of the E2F family transcription factors recently implicated in the control of mouse Raet1 genes in proliferating fibroblasts (56).…”

Section: Discussionmentioning

confidence: 65%

Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

Soriani

Iannitto

Ricci

et al. 2014

The Journal of Immunology

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Increasing evidence indicates that cancer cell stress induced by chemotherapeutic agents promote antitumor immune responses and contribute to their full clinical efficacy. In this article, we identify the signaling events underlying chemotherapy-induced NKG2D and DNAM-1 ligand expression on multiple myeloma (MM) cells. Our findings indicate that sublethal doses of doxorubicin and melphalan initiate a DNA damage response (DDR) controlling ligand upregulation on MM cell lines and patient-derived malignant plasma cells in Chk1/2-dependent and p53-independent manner. Drug-induced MICA and PVR gene expression are transcriptionally regulated and involve DDR-dependent E2F1 transcription factor activity. We also describe the involvement of changes in the redox state in the control of DDR-dependent upregulation of ligand surface expression and gene transcriptional activity by using the antioxidant agent N-acetyl-l-cysteine. Finally, in accordance with much evidence indicating that DDR and oxidative stress are major determinants of cellular senescence, we found that redox-dependent DDR activation upon chemotherapeutic treatment is critical for MM cell entry in premature senescence and is required for the preferential ligand upregulation on senescent cells, which are preferentially killed by NK cells and trigger potent IFN-γ production. We propose immunogenic senescence as a mechanism that promotes the clearance of drug-treated tumor cells by innate effector lymphocytes, including NK cells.

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“…NK cells recognize mouse cancer cells via ribonucleic acid export-1 (RAE-1) family ligands and human cancer via MHC class I-related genes A and B (MICA and MICB), all of which bind the NK cell-activating receptor NKG2D (84,87,88). These NKG2D ligands are upregulated during the DNA damage response and cell cycle progression via E2F transcription factors (89). The antitumor activity of NK cells was mainly observed in hematopoietic malignancies, but it was recently shown that in mice, MULT1, a high-affinity NKG2D ligand that is released by cancer cells, causes NK cell activation and rejection of solid tumors (90).…”

Section: The Good: Immunity and Cancermentioning

confidence: 99%

Immunity, inflammation, and cancer: an eternal fight between good and evil

Shalapour¹,

Karin²

2015

Journal of Clinical Investigation

603

509

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RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry

Abstract: E2F transcription factors regulate expression of RAE-1 family NKG2D ligands in cancer cells and normal proliferating cells to promote wound healing and immune recognition.

Cited by 104 publications

References 47 publications

p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells

p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells

Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

Immunity, inflammation, and cancer: an eternal fight between good and evil

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