{
    "abstract": "ZNF398/ZER6 belongs to the Kr\u00fcppel-associated box (KRAB) domain-containing zinc finger proteins (K-ZNFs), the largest family of transcriptional repressors in higher organisms. ZER6 exists in two isoforms, p52 and p71, generated through alternative splicing. Our investigation revealed that p71-ZER6 is abundantly expressed in the stomach, kidney, liver, heart, and brown adipose tissue, while p52-ZER6 is predominantly found in the stomach and brain. The role of p52-ZER6 in neurons has remained unclear. Leveraging open-source RNA-seq data, we identified metallothionein 3 (MT3) as a target gene of p52-ZER6 in mouse hippocampal neuronal HT-22\u00a0cells. Through chromatin immunoprecipitation assays, we identified the putative DNA-binding motif (CTAGGGGGGTTGTTATCTCTTTGG) of p52-ZER6 in the promoter region of MT3. Furthermore, we demonstrated an interaction between p52-ZER6 and estrogen receptor alpha (ER\u03b1) in the nucleus of SH-SY5Y cells, which led to the inhibition of p52-ZER6's DNA occupancy on the promoter of the MT3 gene. MT3 is a cysteine-rich, low molecular-weight protein known for reducing oxidative stress, reactive oxygen species (ROS), and metal toxicity. Our study revealed that overexpression of p52-ZER6 reduced the levels of MT3, increasing ROS levels, which was mitigated by co-overexpression of ER\u03b1. Notably, we also observed upregulation of p52-ZER6 and reduction of MT3 in the cortex of 5xFAD, an Alzheimer's disease (AD) mouse model. These findings suggest a potential pathological mechanism involving p52-ZER6-mediated ROS production in AD pathogenesis.",
    "authors": [
        {
            "affiliation": "Department of Pharmacology, Republic of Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 440-746, Republic of Korea.",
            "firstname": "Eunsang",
            "initials": "E",
            "lastname": "Kwag"
        },
        {
            "affiliation": "Department of Pharmacology, Republic of Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 440-746, Republic of Korea.",
            "firstname": "Soo Jeong",
            "initials": "SJ",
            "lastname": "Park"
        },
        {
            "affiliation": "Department of Pharmacology, Republic of Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 440-746, Republic of Korea.",
            "firstname": "Jee-Ho",
            "initials": "JH",
            "lastname": "Lee"
        },
        {
            "affiliation": "Department of Pharmacology, Republic of Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 440-746, Republic of Korea.",
            "firstname": "Ji-Yeong",
            "initials": "JY",
            "lastname": "Lee"
        },
        {
            "affiliation": "Department of Pharmacology, Republic of Korea.",
            "firstname": "Rin",
            "initials": "R",
            "lastname": "Khang"
        },
        {
            "affiliation": "Department of Pharmacology, Republic of Korea; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 440-746, Republic of Korea; Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea. Electronic address: jshin24@skku.edu.",
            "firstname": "Joo-Ho",
            "initials": "JH",
            "lastname": "Shin"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2025 Elsevier Inc. All rights reserved.",
    "doi": "10.1016/j.bbrc.2025.151316",
    "journal": "Biochemical and biophysical research communications",
    "keywords": [
        "Alzheimer's disease (AD)",
        "Estrogen receptor alpha (ER\u03b1)",
        "Metallothionein 3 (MT3)",
        "ZNF398/p52-ZER6"
    ],
    "methods": null,
    "publication_date": "2025-01-15",
    "pubmed_id": "39809138",
    "results": null,
    "title": "Upregulation of p52-ZER6 (ZNF398) increases reactive oxygen species by suppressing metallothionein-3 in neuronal cells.",
    "xml": "<Element 'PubmedArticle' at 0x788506f37a60>"
}