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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Targeting Zfp148 activates p53 and reduces tumor initiation in the gut
Anna Nilton1, Volkan I Sayin1,2, Zhiyuan V Zou1
1Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.
Abstract:
The transcription factor Zinc finger protein 148 (Zfp148, ZBP-89, BFCOL, BERF1, htβ) interacts physically with the tumor suppressor p53, but the significance of this interaction is not known. We recently showed that knockout of Zfp148 in mice leads to ectopic activation of p53 in some tissues and cultured fibroblasts, suggesting that Zfp148 represses p53 activity. Here we hypothesize that targeting Zfp148 would unleash p53 activity and protect against cancer development, and test this idea in the APCMin/+ mouse model of intestinal adenomas. Loss of one copy of Zfp148 markedly reduced tumor numbers and tumor-associated intestinal bleedings, and improved survival. Furthermore, after activation of β-catenin-the initiating event in colorectal cancer-Zfp148 deficiency activated p53 and induced apoptosis in intestinal explants of APCMin/+ mice. The anti-tumor effect of targeting Zfp148 depended on p53, as Zfp148 deficiency did not affect tumor numbers in APCMin/+ mice lacking one or both copies of Trp53. The results suggest that Zfp148 controls the fate of newly transformed intestinal tumor cells by repressing p53 and that targeting Zfp148 might be useful in the treatment of colorectal cancer.
Insights
Targeting Zinc finger protein 148 (Zfp148) represses p53 activity, reducing intestinal tumors in mice. This suggests Zfp148 inhibition may offer a new strategy for colorectal cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The transcription factor Zinc finger protein 148 (Zfp148) interacts with the tumor suppressor p53.
- The functional significance of the Zfp148-p53 interaction in cancer is unknown.
- Previous studies suggest Zfp148 may repress p53 activity.
Purpose of the Study:
- To investigate the hypothesis that targeting Zfp148 can unleash p53 activity and protect against intestinal cancer.
- To evaluate the therapeutic potential of Zfp148 inhibition in the APCMin/+ mouse model of intestinal adenomas.
Main Methods:
- Utilized the APCMin/+ mouse model, a standard model for intestinal adenomas.
- Assessed the impact of Zfp148 gene dosage on tumor development, bleeding, and survival.
- Investigated the role of p53 in mediating the anti-tumor effects of Zfp148 deficiency.
- Examined p53 activation and apoptosis induction in intestinal explants following Zfp148 deficiency and beta-catenin activation.
Main Results:
- Reducing Zfp148 copy number significantly decreased intestinal tumor formation and associated bleeding in APCMin/+ mice.
- Zfp148 deficiency led to p53 activation and apoptosis in intestinal explants, particularly after beta-catenin activation.
- The anti-tumor effects of Zfp148 targeting were dependent on the presence of functional p53, as demonstrated in Trp53 knockout mice.
Conclusions:
- Zfp148 acts as a repressor of p53 in the context of intestinal tumorigenesis.
- Zfp148 influences the fate of nascent intestinal tumor cells by inhibiting p53.
- Targeting Zfp148 represents a potential therapeutic strategy for colorectal cancer, contingent on p53 activity.
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