Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

  title={Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation},
  author={Abdalla Akef and K. McGraw and S. Cappell and D. Larson},
U2AF1 forms a heterodimeric complex with U2AF2 that is primarily responsible for 3’ splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome and Acute Myeloid Leukemia, and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). However, the U2AF heterodimer also has a non-canonical function as a translational regulator. Here, we report that the U2AF1 S34F mutation results in specific mis… Expand
The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis
The findings show that IGF2BP3 represents an attractive therapeutic target in this disease, providing important insights into mechanisms of posttranscriptional regulation in leukemia. Expand


The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation.
A noncanonical function of U2AF1 is uncovered, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation, which contributes to metastasis, inflammation, and cancer progression in mice and humans. Expand
The zinc finger domains in U2AF26 and U2AF35 have diverse functionalities including a role in controlling translation
This work reveals unexpected functions of U2AF26/35 and their ZnF domains, thereby contributing to a better understanding of their role and regulation in mammalian cells. Expand
Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival
It is shown that lung adenocarcinoma cell lines bearing U2AF1 mutations do not require the mutant protein for growth in vitro or in vivo, and wild-type U2af1 is required for survival, regardless of whether cells carry the U2 AF1S34F allele. Expand
Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction
The finding that the cell selectively upregulates the translation of mRNAs with a polypyrimidine tract at their 5′-transcriptional start site, including that encoding rpL11, on impairment of 40S ribosome biogenesis, would spare other stress pathways that mediate the potential benefits of p53 induction. Expand
Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal
It appears that AMLs are frequently characterized by gain-of-function mutations of NPM that create functional NES, suggesting that alterations of nuclear export might represent a general mechanism of leukemogenesis and a novel target for therapeutic intervention. Expand
Nucleophosmin regulates the stability and transcriptional activity of p53
It is shown that NPM interacts directly with the tumour suppressor p53, regulates the increase in stability and transcriptional activation of p53 after different types of stress, and induces p53-dependent premature senescence on overexpression in diploid fibroblasts. Expand
A Pan-Cancer Analysis of Transcriptome Changes Associated with Somatic Mutations in U2AF1 Reveals Commonly Altered Splicing Events
It is found that S34F/Y mutations cause preferences for CAG over UAG 3′ splice site sequences, which is consistent with the function of U2AF1 in 3′splice site recognition, and shows consistent effects of U 2AF1 mutation on splicing in distinct cancer cell types. Expand
Importin 7 and exportin 1 link c-Myc and p53 to regulation of ribosomal biogenesis.
It is proposed that c-Myc and p53 counter each other in the regulation of elements within the nuclear transport machinery, thereby exerting opposing effects on the rate of ribosome biogenesis. Expand
Myeloid Leukemia-Associated Nucleophosmin Mutants Perturb p53-Dependent and Independent Activities of the Arf Tumor Suppressor Protein
P perturbation of Arf function appears to be insufficient to explain the oncogenic effects of the NPMc mutation, and the idea that NPMC also contrib-utes to AML by dominantly perturbing other functions of the wild type NPM protein is favored. Expand
Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation.
It is shown that ARF interacts with B23, a multifunctional nucleolar protein involved in ribosome biogenesis, and promotes its polyubiquitination and degradation, and suggests a nucleolar role of ARF in surveillance of oncogenic insults. Expand