KCTD1 mutants in scalp‑ear‑nipple syndrome and AP‑2α P59A in Char syndrome reciprocally abrogate their interactions, but can regulate Wnt/β‑catenin signaling

Abstract

Potassium-channel tetramerization-domaincontaining 1 (KcTd1) mutations are reported to result in scalp-ear-nipple syndrome. These mutations occur in the conserved broad-complex, tramtrack and bric a brac domain, which is associated with inhibited transcriptional activity. However, the mechanisms of KcTd1 mutants have not previously been elucidated; thus, the present study aimed to investigate whether KcTd1 mutants affect their interaction with transcription factor aP-2α and their regulation of the Wnt pathway. results from the present study demonstrated that none of the ten KcTd1 mutants had an inhibitory effect on the transcriptional activity of aP-2α. co-immunoprecipitation assays demonstrated that certain mutants exhibited changeable localization compared with the nuclear localization of wild-type KcTd1, but no KcTd1 mutant interacted with aP-2α. almost all KcTd1 mutants, except KcTd1 a30e and H33Q, exhibited differential inhibitory effects on regulating ToPFlaSH luciferase reporter activity. in addition, the interaction region of KcTd1 to the PY motif (amino acids 59-62) in aP-2α was identified. KcTd1 exhibited no suppressive effects on the transcriptional activity of the aP-2α P59a mutant, resulting in char syndrome, a genetic disorder characterized by a distinctive facial appearance, heart defect and hand abnormalities, by altered protein cellular localization that abolished protein interactions. However, the P59a, P60a, P61r and 4a aP-2α mutants inhibited ToPFlaSH reporter activity. Moreover, aP-2α and KcTd1 inhibited β-catenin expression levels and SW480 cell viability. The present study thus identified a putative mechanism of disease-related KcTd1 mutants and aP-2α mutants by disrupting their interaction with the wildtype proteins aP-2α and KCTD1 and influencing the regulation of the Wnt/β-catenin pathway.

Determination of WWOX Function in Modulating Cellular Pathways Activated by AP-2α and AP-2γ Transcription Factors in Bladder Cancer

“…The identification of AP-2 targets and their functional annotation provided an insight into the signaling pathways in which they are involved. The data on the role of WWOX, AP-2α and AP-2γ in the regulation of MAPK [22][23][24], Wnt [25][26][27], Ras [28][29][30] and PI3K-Akt [31][32][33] signaling are available; however, no influence on Rap1 signaling was found in the literature, suggesting that these could be novel observations. Aside from signal transduction, WWOX and two AP-2 factors are implicated in adhesion [34][35][36], migration [24,37,38], axon guidance (indirectly) [39][40][41] and regulation of extracellular matrix [42][43][44] or miRNA [45,46].…”

“…The identification of AP-2 targets and their functional annotation provided an insight into the signaling pathways in which they are involved. The data on the role of WWOX, AP-2α and AP-2γ in the regulation of MAPK [22][23][24], Wnt [25][26][27], Ras [28][29][30] and PI3K-…”

Identification of SOX18 as a New Gene Predisposing to Congenital Heart Disease

“…In humans, loss-of-function alterations in both SOX7 and SOX17 have been related to CHD [ 73 , 78 ]. Moreover, mutations in TFAP2B have been reported to cause syndromic PDA by interfering with the inhibitory effect of TFAP2B on the canonical Wnt/β-catenin signaling pathway [ 95 ]. Given that all of the Xenopus, murine and human SOXF factors have a conserved β-catenin binding domain at the C-terminus and interact with β-catenin to repress the activity of β-catenin/TCF transcriptional complexes, and therefore suppress the Wnt/β-catenin signaling [ 86 ], the SOX18 mutation identified in our study contributed to PDA probably by a similar mechanism.…”

Therapeutic Response-Based Reclassification of Multiple Tumor Subtypes Reveals Intrinsic Molecular Concordance of Therapy Across Histologically Disparate Cancers

“…In our analysis, KCTD1_PCAT18, TNFRSF9, and LTB, as the top three most connected genes, were worth for further investigation. KCTD1 (potassium channel tetramerization domain containing 1) was reported to regulate the Wnt/β-catenin pathway ( Li et al, 2014 ; Hu et al, 2020 ), and PCAT18 (prostate cancer-associated transcript 18, lncRNA), was found to promote the progression of colorectal or gastric cancer through miR-759 or miR-135b ( Hu et al, 2020 ; Zhang et al, 2020 ), thus KCTD1_PCAT18 fusion may resulting in the development of cancer. TNFRSF9 (tumor necrosis factor receptor superfamily member 9), also known as 4-1BB and CD137, is an immune co-stimulatory receptor.…”