Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis.
A Kinase Anchor Proteins
/ chemistry
Animals
Carcinogenesis
/ genetics
Cell Transformation, Neoplastic
/ genetics
Cells, Cultured
Cellular Senescence
/ genetics
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Nuclear Proteins
/ chemistry
Phase Transition
RNA Splicing
/ physiology
Structure-Activity Relationship
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
02
07
2019
accepted:
24
06
2020
pubmed:
29
7
2020
medline:
27
10
2020
entrez:
29
7
2020
Statut:
ppublish
Résumé
It remains unknown if biophysical or material properties of biomolecular condensates regulate cancer. Here we show that AKAP95, a nuclear protein that regulates transcription and RNA splicing, plays an important role in tumorigenesis by supporting cancer cell growth and suppressing oncogene-induced senescence. AKAP95 forms phase-separated and liquid-like condensates in vitro and in nucleus. Mutations of key residues to different amino acids perturb AKAP95 condensation in opposite directions. Importantly, the activity of AKAP95 in splice regulation is abolished by disruption of condensation, significantly impaired by hardening of condensates, and regained by substituting its condensation-mediating region with other condensation-mediating regions from irrelevant proteins. Moreover, the abilities of AKAP95 in regulating gene expression and supporting tumorigenesis require AKAP95 to form condensates with proper liquidity and dynamicity. These results link phase separation to tumorigenesis and uncover an important role of appropriate biophysical properties of protein condensates in gene regulation and cancer.
Identifiants
pubmed: 32719551
doi: 10.1038/s41556-020-0550-8
pii: 10.1038/s41556-020-0550-8
pmc: PMC7425812
mid: NIHMS1606946
doi:
Substances chimiques
A Kinase Anchor Proteins
0
AKAP8 protein, human
0
Akap8 protein, mouse
0
Nuclear Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
960-972Subventions
Organisme : NIH HHS
ID : S10 OD016446
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103540
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
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