ZBP-89 function in colonic stem cells and during butyrate-induced senescence

Ocadiz-Ruiz, Ramon; Photenhauer, Amanda; Hayes, Michael M.; Ding, Lin; Fearon, Eric R.; Merchant, Juanita L.

doi:10.18632/oncotarget.21698

Cited by 14 publications

(15 citation statements)

References 37 publications

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“…Thus, deletion of Zfp148 may activate p53 by derepressing ARF transcription, similar to knockouts of polycomb members Bmi1, M33, Mel18, and Phc2 28 – 31 . In line with this, inhibition of ZNF148 potentiates butyrate-induced senescence of human HT116 colon cancer cells by derepressing the p16 promoter 32 . However, increased expression of ARF could have many underpinnings.…”

Section: Discussionsupporting

confidence: 63%

“…Without evidence of genetic interaction between ZNF148 and TP53 in human cancer cells, the incentive for therapeutic targeting of ZNF148 becomes weak. The recent finding that inhibition of ZNF148 potentiates butyrate-induced senescence of human HT116 colon cancer cells 32 suggests that core functions of Zfp148 are evolutionarily conserved. Further investigation of the interaction between Zfp148 and Cdkn2a promoters may provide valuable mechanistic insights.…”

Section: Discussionmentioning

confidence: 99%

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Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway

Zou

Gul

Lindberg

et al. 2020

Sci Rep

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Recent data suggest that the transcription factor Zfp148 represses activation of the tumor suppressor p53 in mice and that therapeutic targeting of the human orthologue ZNF148 could activate the p53 pathway without causing detrimental side effects. We have previously shown that Zfp148 deficiency promotes p53-dependent proliferation arrest of mouse embryonic fibroblasts (MEFs), but the underlying mechanism is not clear. Here, we showed that Zfp148 deficiency downregulated cell cycle genes in MEFs in a p53-dependent manner. Proliferation arrest of Zfp148-deficient cells required increased expression of ARF, a potent activator of the p53 pathway. Chromatin immunoprecipitation showed that Zfp148 bound to the ARF promoter, suggesting that Zfp148 represses ARF transcription. However, Zfp148 preferentially bound to promoters of other transcription factors, indicating that deletion of Zfp148 may have pleiotropic effects that activate ARF and p53 indirectly. In line with this, we found no evidence of genetic interaction between TP53 and ZNF148 in cRiSpR and siRnA screen data from hundreds of human cancer cell lines. We conclude that Zfp148 deficiency, by increasing ARF transcription, downregulates cell cycle genes and cell proliferation in a p53-dependent manner. However, the lack of genetic interaction between ZNF148 and TP53 in human cancer cells suggests that therapeutic targeting of ZNF148 may not increase p53 activity in humans. Activation of the tumor suppressor p53 may have beneficial effects on tumors with wild-type p53 1. The first drugs targeting the p53 repressor murine double minute 2 (MDM2) have entered clinical trials, but their clinical benefit is still under evaluation 2. Because knockout of Mdm2 in mice causes widespread and lethal activation of p53 in normal tissues 3 , efficient pharmacological inhibition of MDM2 may have adverse effects. Thus, identifying alternative ways to activate the p53 pathway with less adverse effects is warranted. Zinc finger protein 148 (Zfp148, Zbp-89, BFCOL, BERF1, htβ) is a transcription factor that binds to GC-rich DNA sequences, thus activating or repressing transcription of target genes 4-11. Earlier studies have shown that Zfp148 is a potent repressor of p53 activity in mice. Firstly, deletion of Zfp148 caused p53-dependent proliferation arrest of cultured mouse embryonic fibroblasts (MEFs) and prenatal lung tissue that was rescued by reducing oxidative stress 12. Moreover, deletion of one copy of Zfp148 in the Apc Min/+ model of intestinal adenomas reduced tumor numbers and increased survival by increasing p53 activity 13. In line with this, conditional deletion of one or both alleles of Zfp148 in the gut epithelium of Apc FL/+ mice reduced tumor formation through a mechanism

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway

Zou

Gul

Lindberg

et al. 2020

Sci Rep

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“…Oncogenic RNF43 mutations induce a TP53-dependent growth arrest in human colon organoids Next, we investigated the impact of oncogenic RNF43 truncations on epithelial homeostasis, using human colon organoids (Jung et al, 2011;Sato et al, 2011). Introduction of CRISPR/Cas9-mediated frame shift mutations within the oncogenic region of the endogenous RNF43 locus (onco-RNF43) yielded only a limited number of small organoid clones that failed to thrive, reminiscent of a senescent phenotype (Fig EV2A and Appendix Fig S2A;Ocadiz-Ruiz et al, 2017). Genotyping of a slowly expanding clone confirmed the presence of a mono-allelic onco-RNF43 mutation (Appendix Fig S2B).…”

Section: Ck1-mediated Phosphorylation Of the Truncated Rnf43 Cytosolimentioning

confidence: 99%

RNF 43 truncations trap CK 1 to drive niche‐independent self‐renewal in cancer

et al. 2020

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Wnt/β‐catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt‐hypersensitive tumors that are susceptible to anti‐Wnt‐based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce β‐catenin‐mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin‐independent suppressor role of the RNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing β‐catenin turnover and propelling ligand‐independent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche‐independent program for self‐renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti‐Wnt‐based therapy. Our data demonstrate the relevance of studying patient‐derived mutations for understanding disease mechanisms and improved applications of precision medicine.

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“…46) (47,48). Additionally, the promoters for a handful of these candidates, including Psph and Pdk4, bind to ZFP148 in mouse cell lines (49). The predicted direct transcriptional targets of ZFP148 suggest a possible mechanism to explain the altered glucose and amino acid sensitivity of the β-Zfp148 KO islets.…”

Section: Resultsmentioning

confidence: 98%