Reciprocal negative regulation between the tumor suppressor protein p53 and B cell CLL/lymphoma 6 (BCL6) via control of caspase-1 expression

Kim, Min-Kyeong; Song, Jiwoon; Koh, Dong-In; Kim, Jin Young; Hatano, Masahiko; Jeon, Bu‐Nam; Kim, Minyoung; Cho, Su-Yeon; Kim, Kyung‐Sup; Hur, Man‐Wook

doi:10.1074/jbc.ra118.004204

Cited by 15 publications

(10 citation statements)

References 41 publications

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“…Additionally, we found that BACH2 RNA expression was negatively correlated with CD38 expression (Pearson’s r = −0.418, p -value = 0.011) ( Table S3A ), which is a marker for an unfavourable prognosis in CLL, which correlates with the BCR signalling response, activation, and proliferation [ 21 ]. BCL6 inhibits the expression of p53 and regulates the DNA damage-induced apoptotic responses in GC B-cells [ 22 , 23 , 24 ]; thus, we also studied the link between TP53 mutations and RNA expressions of BCL6 and BACH2 , which showed no correlation, implying TP53-independent functions for these regulators in CLL ( Table S3A,B ).…”

Section: Resultsmentioning

confidence: 99%

Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia

Ciardullo

Szołtysek

Zhou

et al. 2021

Cancers

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Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell regulators, BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) and BCL6 (B-cell CLL/lymphoma 6), in a cohort of 102 CLL patients and determined the protein interaction networks that they participate in using MEC-1 CLL cells. We observed that CLL patients expressing low levels of BCL6 and BACH2 RNA had significantly shorter overall survival (OS) than high BCL6- and BACH2-expressing cases. Notably, their low expression specifically decreased the OS of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Similar to the RNA data, a low BACH2 protein expression was associated with a significantly shorter OS than a high expression. There was no direct interaction observed between BACH2 and BCL6 in MEC-1 CLL cells, but they shared protein networks that included fifty different proteins. Interestingly, a prognostic index (PI) model that we generated, using integrative risk score values of BACH2 RNA expression, age, and 17p deletion status, predicted patient outcomes in our cohort. Taken together, these data have shown for the first time a possible prognostic role for BACH2 in CLL and have revealed protein interaction networks shared by BCL6 and BACH2, indicating a significant role for BACH2 and BCL6 in key cellular processes, including ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology.

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Section: Resultsmentioning

confidence: 99%

Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia

Ciardullo

Szołtysek

Zhou

et al. 2021

Cancers

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“…Further investigation is required to determine whether apoptosis influences measures of radiation-induced expression of IRF1 and STAT1 . The activation of STAT and TP53 signaling has also been found in response to etoposide [36,37] and several other genotoxic drugs, such as fludarabine or doxorubicin [38]. The critical importance of STAT1 is demonstrated in the mutations of the STAT1 gene in humans.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell RNA-Sequencing Identifies Activation of TP53 and STAT1 Pathways in Human T Lymphocyte Subpopulations in Response to Ex Vivo Radiation Exposure

Moreno‐Villanueva

Zhang

Feiveson

et al. 2019

IJMS

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Detrimental health consequences from exposure to space radiation are a major concern for long-duration human exploration missions to the Moon or Mars. Cellular responses to radiation are expected to be heterogeneous for space radiation exposure, where only high-energy protons and other particles traverse a fraction of the cells. Therefore, assessing DNA damage and DNA damage response in individual cells is crucial in understanding the mechanisms by which cells respond to different particle types and energies in space. In this project, we identified a cell-specific signature for radiation response by using single-cell transcriptomics of human lymphocyte subpopulations. We investigated gene expression in individual human T lymphocytes 3 h after ex vivo exposure to 2-Gy gamma rays while using the single-cell sequencing technique (10X Genomics). In the process, RNA was isolated from ~700 irradiated and ~700 non-irradiated control cells, and then sequenced with ~50 k reads/cell. RNA in each of the cells was distinctively barcoded prior to extraction to allow for quantification for individual cells. Principal component and clustering analysis of the unique molecular identifier (UMI) counts classified the cells into three groups or sub-types, which correspond to CD4+, naïve, and CD8+/NK cells. Gene expression changes after radiation exposure were evaluated using negative binomial regression. On average, BBC3, PCNA, and other TP53 related genes that are known to respond to radiation in human T cells showed increased activation. While most of the TP53 responsive genes were upregulated in all groups of cells, the expressions of IRF1, STAT1, and BATF were only upregulated in the CD4+ and naïve groups, but were unchanged in the CD8+/NK group, which suggests that the interferon-gamma pathway does not respond to radiation in CD8+/NK cells. Thus, single-cell RNA sequencing technique was useful for simultaneously identifying the expression of a set of genes in individual cells and T lymphocyte subpopulation after gamma radiation exposure. The degree of dependence of UMI counts between pairs of upregulated genes was also evaluated to construct a similarity matrix for cluster analysis. The cluster analysis identified a group of TP53-responsive genes and a group of genes that are involved in the interferon gamma pathway, which demonstrate the potential of this method for identifying previously unknown groups of genes with similar expression patterns.

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“…Various combinations of pGL2‐ SIRT1 ‐Luc, pcDNA3.0‐ HIC1 , pcDNA3.1‐ HIC2 , pcDNA3.1‐ CtBP , pcDNA3.1‐ p300 , or control vector were transiently transfected into HEK293A cells using Lipofectamine Plus reagent (Invitrogen, Carlsbad, CA, USA). Transient transcription analysis was performed as previously reported .…”

Section: Methodsmentioning

confidence: 99%

“…Western blotting was performed as previously described . Antibodies against the following antigens were used: FLAG tag (Sigma, St. Louis, MO, USA, F3165), His tag (R&D Systems, Minneapolis, MN, USA, MAB050), Myc tag (Cell Signaling #2278), HIC1 (Santa Cruz, Heidelberg, Germany, sc‐271499), HIC2 (Thermo Fisher Scientific, Rockford, IL, USA, PA5‐37293), SIRT1 (Millipore, Temecula, CA, USA, 07‐131), p300 (Millipore 05‐257), acetylated‐lysine (Cell Signaling #9441), and GAPDH (Santa Cruz sc‐32233).…”

Section: Methodsmentioning

confidence: 99%

“…HIC1 and HIC2 polypeptides were prepared by incubating 2 μg of either pcDNA3.0‐FLAG‐HIC1 or pcDNA3.1‐His‐HIC2, with T N T Quick‐Coupled Transcription/Translation Extract (Promega) containing 40 μL T N T Quick Master Mix and 2 μL [ 35 S]‐methionine (1175.0 Ci/mol, PerkinElmer Life Sciences, Waltham, MA, USA), at 30 °C for 90 min. We then performed GST‐fusion protein pull‐down assays, as previously described .…”

Section: Methodsmentioning

confidence: 99%

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HIC2, a new transcription activator of SIRT1

et al. 2019

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The protein deacetylase SIRT1 is crucial to numerous physiological processes, such as aging, metabolism, and autoimmunity, and is repressed by various transcription factors, including HIC1. Conversely, we found that HIC2, which is highly homologous to HIC1, is a transcriptional activator of SIRT1 due to opposite activity of the intermediate domains of the two homologs. Importantly, this relationship between HIC2 and SIRT1 could be important for cardiac development, where both proteins are implicated. Here, we assessed whether ectopic expression of HIC2, and subsequent upregulation of SIRT1, might decrease apoptosis in H9c2 cardiomyocytes under simulated ischemia/reperfusion (I/R) injury conditions. Our results demonstrate that unlike its structural homolog HIC1, HIC2 is a pivotal transcriptional activator of SIRT1 and, consequently, may protect the heart from I/R injury.

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Reciprocal negative regulation between the tumor suppressor protein p53 and B cell CLL/lymphoma 6 (BCL6) via control of caspase-1 expression

Cited by 15 publications

References 41 publications

Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia

Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia

Single-Cell RNA-Sequencing Identifies Activation of TP53 and STAT1 Pathways in Human T Lymphocyte Subpopulations in Response to Ex Vivo Radiation Exposure

HIC2, a new transcription activator of SIRT1

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