ZNF224 Protein: Multifaceted Functions Based on Its Molecular Partners.

Elena Cesaro,Roberta Rapuano,Arianna Pastore,Paola Costanzo,Angelo Lupo,Michela Grosso

doi:10.3390/molecules26206296

Elena Cesaro, Roberta Rapuano + Show 4 more

Open Access

https://doi.org/10.3390/molecules26206296

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Abstract

The transcription factor ZNF224 is a Kruppel-like zinc finger protein that consists of 707 amino acids and contains 19 tandemly repeated C2H2 zinc finger domains that mediate DNA binding and protein–protein interactions. ZNF224 was originally identified as a transcriptional repressor of genes involved in energy metabolism, and it was demonstrated that ZNF224-mediated transcriptional repression needs the interaction of its KRAB repressor domain with the co-repressor KAP1 and its zinc finger domains 1–3 with the arginine methyltransferase PRMT5. Furthermore, the protein ZNF255 was identified as an alternative isoform of ZNF224 that possesses different domain compositions mediating distinctive functional interactions. Subsequent studies showed that ZNF224 is a multifunctional protein able to exert different transcriptional activities depending on the cell context and the variety of its molecular partners. Indeed, it has been shown that ZNF224 can act as a repressor, an activator and a cofactor for other DNA-binding transcription factors in different human cancers. Here, we provide a brief overview of the current knowledge on the multifaceted interactions of ZNF224 and the resulting different roles of this protein in various cellular contexts.

Highlights

Zinc finger proteins (ZFPs) are the most extended group of regulators in mammals and are involved in the control of transcription through the binding of their C2H2 domains to the specific DNA sequences lying in the promoter region of target genes [1,2]
We focus on some properties of KRAB-ZFPs through the description of specific structural features and protein–protein interactions of one member of this protein family, ZNF224, and the relative resulting functional abilities of this multifaceted protein
We demonstrated that ZNF224 is a mediator of apoptosis induced by ara-C and imatinib acting as a transcriptional co-factor of the Wilms tumor protein 1 (WT1) in the modulation of apoptotic genes and directly repressing the expression of the oncogenes c-myc and Axl, both of which are involved in oncogenic transformation and drug resistance in chronic myeloid leukemia (CML) [24,25,26,27,28]

Summary

Introduction

Zinc finger proteins (ZFPs) are the most extended group of regulators in mammals and are involved in the control of transcription through the binding of their C2H2 domains to the specific DNA sequences lying in the promoter region of target genes [1,2]. Comparison between the different KRAB domains and analysis of in vitro gene expression studies allowed for the definition of a consensus amino acid sequence required for the2foufl1l4 repression of their target genes [7,8] Among these domains, the KRAB domain, located in the NH2-terminus of most C zinc finger proteins, shows very strong transcriptional inhibitory activity towards the get genes to which the KRAB-containing zinc finger proteins (KRAB-ZFPs) bind [7,8]. Analysis of the gene expression of around 800 structurally different KRAB-ZFPs generated by 400 genes present in the human genome contributed to clarifying various aspects of the structure/function dichotomy concerning the KRAB-ZFP family, revealing, sometimes, a various and multifaceted landscape During these years, a comparison of the KRAB-ZFP sequences revealed that they contain, on average, from 12 to 30 zinc finger domains that allow efficient binding to the canonical DNA-binding motif on the promoter region of their target genes [17,18]. We focus on some properties of KRAB-ZFPs through the description of specific structural features and protein–protein interactions of one member of this protein family, ZNF224, and the relative resulting functional abilities of this multifaceted protein

The Human ZNF224

ZNF224 and ZNF255

ZNF224

Findings

Conclusions