title: Aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms control lymphoid cancer cell proliferation through differentially regulating tumor suppressor p53 activity.
abstract: The aryl hydrocarbon receptor nuclear translocator (ARNT) is involved in xenobiotic and hypoxic responses, and we previously showed that ARNT also regulates nuclear factor-κB (NF-κB) signaling by altering the DNA binding activity of the RelB subunit. However, our initial study of ARNT-mediated RelB modulation was based on simultaneous suppression of the two ARNT isoforms, isoform 1 and 3, and precluded the examination of their individual functions. We find here that while normal lymphocytes harbor equal levels of isoform 1 and 3, lymphoid malignancies exhibit a shift to higher levels of ARNT isoform 1. These elevated levels of ARNT isoform 1 are critical to the proliferation of these cancerous cells, as suppression of isoform 1 in a human multiple myeloma (MM) cell line, and an anaplastic large cell lymphoma (ALCL) cell line, triggered S-phase cell cycle arrest, spontaneous apoptosis, and sensitized cells to doxorubicin treatment. Furthermore, co-suppression of RelB or p53 with ARNT isoform 1 prevented cell cycle arrest and blocked doxorubicin induced apoptosis. Together our findings reveal that certain blood cancers rely on ARNT isoform 1 to potentiate proliferation by antagonizing RelB and p53-dependent cell cycle arrest and apoptosis. Significantly, our results identify ARNT isoform 1 as a potential target for anticancer therapies.
authors.affiliation: Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Kacie A
authors.initials: KA
authors.lastname: Gardella
authors.affiliation: Division of Pharmacology and Toxicology, and The Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Israel
authors.initials: I
authors.lastname: Muro
authors.affiliation: Division of Pharmacology and Toxicology, and The Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Fang
authors.affiliation: Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Krishnakali
authors.initials: K
authors.lastname: Sarkar
authors.affiliation: Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Omayra
authors.initials: O
authors.lastname: Mendez
authors.affiliation: Division of Pharmacology and Toxicology, and The Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.|Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Casey W
authors.initials: CW
authors.lastname: Wright
mesh_terms: D017398:Alternative Splicing; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C497396:ARNT protein, human; D020033:Protein Isoforms; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004317:Doxorubicin
keywords: ARNT; RelB; alternative splicing; lymphoid malignancies; p53