FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity.
Amino Acids
/ metabolism
DNA
/ metabolism
Forkhead Box Protein O1
/ chemistry
HEK293 Cells
Humans
Loss of Function Mutation
Lymphoma, B-Cell
/ genetics
Phosphorylation
/ genetics
Point Mutation
Protein Binding
Protein Conformation, alpha-Helical
Protein Domains
/ genetics
Protein Interaction Maps
/ genetics
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
/ genetics
Transcriptional Activation
Transfection
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
25 01 2022
25 01 2022
Historique:
received:
24
09
2021
accepted:
11
01
2022
entrez:
26
1
2022
pubmed:
27
1
2022
medline:
5
3
2022
Statut:
epublish
Résumé
Somatic point mutations of the FOXO1 transcription factor were reported in non-Hodgkin lymphoma including diffuse large B-cell lymphoma, follicular lymphoma and Burkitt lymphoma. These alterations were associated with a poor prognosis and resistance to therapy. Nearly all amino acid substitutions are localized in two major clusters, affecting either the N-terminal region (Nt mutations) or the forkhead DNA-binding domain (DBD mutations). While recent studies have focused on Nt mutations, we characterized FOXO1 DBD mutants. We analyzed their transcriptional activity, DNA binding, phosphorylation and protein-protein interaction. The majority of DBD mutants showed a decrease in activity and DNA binding, while preserving AKT phosphorylation and interaction with the cytoplasmic ATG7 protein. In addition, we investigated the importance of conserved residues of the α-helix 3 of the DBD. Amino acids I213, R214, H215 and L217 appeared to be crucial for FOXO1 activity. Our data underlined the key role of multiple amino-acid residues of the forkhead domain in FOXO1 transcriptional activity and revealed a new type of FOXO1 loss-of-function mutations in B-cell lymphoma.
Identifiants
pubmed: 35079069
doi: 10.1038/s41598-022-05334-4
pii: 10.1038/s41598-022-05334-4
pmc: PMC8789783
doi:
Substances chimiques
Amino Acids
0
FOXO1 protein, human
0
Forkhead Box Protein O1
0
DNA
9007-49-2
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1309Subventions
Organisme : Fonds De La Recherche Scientifique - FNRS
ID : FC29845
Organisme : Actions de recherche Concertées
ID : ARC16/21-073
Informations de copyright
© 2022. The Author(s).
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