title: Targeting Zfp148 activates p53 and reduces tumor initiation in the gut.
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.
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Nilton
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.|Department of Biochemistry, Institute of Biomedicine, Gothenburg, Sweden.
authors.forename: Volkan I
authors.initials: VI
authors.lastname: Sayin
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.
authors.forename: Zhiyuan V
authors.initials: ZV
authors.lastname: Zou
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.
authors.forename: Sama I
authors.initials: SI
authors.lastname: Sayin
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bondjers
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.
authors.forename: Nadia
authors.initials: N
authors.lastname: Gul
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Agren
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Fogelstrand
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology and Genetics, Gothenburg, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Nilsson
authors.affiliation: Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Sweden.|Department of Biochemistry, Institute of Biomedicine, Gothenburg, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Lindahl
mesh_terms: D000236:Adenoma / Q000401:mortality / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000401:mortality / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D006471:Gastrointestinal Hemorrhage / Q000401:mortality / Q000473:pathology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000401:mortality / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C491741:Zfp148 protein, mouse; D051176:beta Catenin
keywords: apoptosis; intestinal tumors; tumor suppressor p53