The Aryl Hydrocarbon Nuclear Translocator Alters CD30-Mediated NF-κB–Dependent Transcription

Wright, Casey W.; Duckett, Colin S.

doi:10.1126/science.1162818

Cited by 54 publications

(69 citation statements)

References 27 publications

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“…11), in support of the latter model. Although no report has shown that GATA3 functions in a manner other than as a classical DNA binding transcription factor (as does, for example, Scl/Tal1 [65] or the aryl hydrocarbon nuclear translocator [66]), such a binary function for GATA3 cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Sekiguchi

Panwar

et al. 2017

Molecular and Cellular Biology

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Allelic exclusion describes the essential immunological process by which feedback repression of sequential DNA rearrangements ensures that only one autosome expresses a functional T or B cell receptor. In wild-type mammals, approximately 60% of cells have recombined the DNA of one T cell receptor ␤ (TCR␤) V-to-DJ-joined allele in a functional configuration, while the second allele has recombined only the DJ sequences; the other 40% of cells have recombined the V to the DJ segments on both alleles, with only one of the two alleles predicting a functional TCR␤ protein. Here we report that the transgenic overexpression of GATA3 leads predominantly to biallelic TCR␤ gene (Tcrb) recombination. We also found that wild-type immature thymocytes can be separated into distinct populations based on intracellular GATA3 expression and that GATA3 LO cells had almost exclusively recombined only one Tcrb locus (that predicted a functional receptor sequence), while GATA3 HI cells had uniformly recombined both Tcrb alleles (one predicting a functional and the other predicting a nonfunctional rearrangement). These data show that GATA3 abundance regulates the recombination propensity at the Tcrb locus and provide new mechanistic insight into the historic immunological conundrum for how Tcrb allelic exclusion is mediated.KEYWORDS allelic exclusion, T cell receptor beta locus, GATA3, monoallelic-tobiallelic switch O ne enduring mystery in cellular immunology regards the underlying mechanisms that control antigen receptor allelic exclusion (1, 2), the process whereby B or T lymphocytes are programmed to express only one functional allele for each chain of their respective antigen receptors (B cell receptor [BCR] or T cell receptor [TCR]), thus avoiding the coexistence of multiple antigen specificities in a single immune cell. Lymphocytes acquire the diversity of antigen recognition (3) as well as a unique monospecificity for particular antigens (4) during development in the bone marrow (B cells) or the thymus (T cells).T lymphocyte development is generally characterized by division into multiple stages based on developmental timing and the location and expression of specific cell surface markers (5). T cell development begins when multipotential hematopoietic progenitor cells in the bone marrow migrate through the bloodstream to the thymus, where early T lineage progenitors (ETPs) are generated and later specified to become T cells (6-10). ETPs differentiate into double-negative (DN) cells (DN2 to DN4 stages) that express neither the CD4 nor the CD8 coreceptor, then into double-positive (DP)

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Section: Discussionmentioning

confidence: 99%

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Sekiguchi

Panwar

et al. 2017

Molecular and Cellular Biology

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“…Recently, an intra-cytoplasmic interaction of HIF1 with CD30 has been identified in ALK þ TCL cells resulting in the modulation of nuclear factor-kB activity (Wright and Duckett, 2009). However, only HIF1a, or the aryl hydrocarbon nuclear translocator, was involved in the complex.…”

Section: Npm/alk-stat3 Pathway Induces Hif1a Expression M Marzec Et Almentioning

confidence: 99%

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

et al. 2010

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“…Moreover, ARNT might also promote survival and proliferation of tumor cells, independently of its roles in AhR and HIF signaling. For example, it has been reported that ARNT increases binding of RelB to DNA (reflecting activation of the non‐canonical NF‐κB pathway) to block the activity of RelA‐p50 dimers, indicating inhibition of the canonical NF‐κB pathway 17. Furthermore, unlike normal lymphocytes that express equal levels of 2 ARNT isoforms (isoforms 1 and 3), malignant lymphoid cell lines (eg, human MM and anaplastic large cell lymphoma cells) exhibit higher levels of isoform 1, which might potentiate cell proliferation by antagonizing RelB and p53‐dependent cell cycle arrest and apoptosis 18.…”

Section: Introductionmentioning

confidence: 99%

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

Yang

Liu

et al. 2018

Cancer Medicine

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Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.

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The Aryl Hydrocarbon Nuclear Translocator Alters CD30-Mediated NF-κB–Dependent Transcription

Cited by 54 publications

References 27 publications

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

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