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Review
. 2023 Sep;28(9):629-641.
doi: 10.1111/gtc.13057. Epub 2023 Jul 25.

The impact of SETBP1 mutations in neurological diseases and cancer

Naoki Kohyanagi  1 , Takashi Ohama  1
Affiliations
Review

The impact of SETBP1 mutations in neurological diseases and cancer

Naoki Kohyanagi et al. Genes Cells. 2023 Sep.

Erratum in

Abstract

SE translocation (SET) is a cancer-promoting factor whose expression is upregulated in many cancers. High SET expression positively correlates with a poor cancer prognosis. SETBP1 (SET-binding protein 1/SEB/MRD29), identified as SET-binding protein, is the causative gene of Schinzel-Giedion syndrome, which is characterized by severe intellectual disability and a distorted facial appearance. Mutations in these genetic regions are also observed in some blood cancers, such as myelodysplastic syndromes, and are associated with a poor prognosis. However, the physiological role of SETBP1 and the molecular mechanisms by which the mutations lead to disease progression have not yet been fully elucidated. In this review, we will describe the current epidemiological data on SETBP1 mutations and shed light on the current knowledge about the SET-dependent and -independent functions of SETBP1.

Keywords: PP2A; SET; SETBP1; cancer; neurological disease.

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Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this paper.

Figures

FIGURE 1
FIGURE 1
The structure of SET and SETBP1. (a) Schematic representation of SETα isoform. SETBP1 directly associates with 195–236 amino acid residues of SETα. (b) Schematic representation of SETBP1. The residues of canonical degron are located in the SKI region. Hotspot mutations observed in SGS patients are indicated by the arrowhead.
FIGURE 2
FIGURE 2
SET‐dependent and ‐independent functions of SETBP1. (a) SETBP1 stabilizes SET protein by blocking SET cleavage by proteases, such as granzyme A (GzmA) and asparaginyl endopeptidase (AEP), as well as autophagic degradation. As SET directly associates with PP2A and inhibits its phosphatase activity, SET accumulation by SETBP1 affects global phosphorylation signals. SET also functions as a histone chaperone. Therefore, SETBP1 may be involved in epigenetic regulation. (b) SETBP1 associates with AT‐rich promoter region and recruits the KMT2A complex. This causes methylation of Lys4 of histone H3 (H3K4me) and induces HOXA9/10 expression.
FIGURE 3
FIGURE 3
SETBP1 expression and prognosis of cancer patients. Kaplan–Meier curves for SETBP1 expression and 10‐year survival. TCGA dataset for (a) urothelial bladder carcinoma (BLCA), (b) stomach adenocarcinoma (STAD), (c) kidney renal clear cell carcinoma (KIRC), and (d) low‐grade glioma (LGG).
FIGURE 4
FIGURE 4
Regulation of SETBP1 transcription. Tripartite motif‐containing 29 (TRIM29) promotes the expression of the transcriptional factor VEZF1. VEZF directly binds to the SETBP1 promoter region and induces SETBP1 transcription. Transcriptional factor EVI‐1 directly or indirectly induces SETBP1 expression. The expression of EVI‐1 is positively and negatively regulated by SETBP1 and RUNX1, respectively.
See this image and copyright information in PMC

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