Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer.
Cancer Cell
; 38(2): 198-211.e8, 2020 08 10.
Article
em En
| MEDLINE
| ID: mdl-32559497
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Transdução de Sinais
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Splicing de RNA
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Proteína Supressora de Tumor p53
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Proteínas Proto-Oncogênicas p21(ras)
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Carcinoma Ductal Pancreático
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Mutação
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article