Browsing by Subject "Neoplasm proteins"

Now showing 1 - 3 of 3
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    Different Roles of TM5, TM6, and ECL3 in the Oligomerization and Function of Human ABCG2
    (American Chemical Society, 2012-05) Mo, Wei; Qi, Jing; Zhang, Jian-Ting; Pharmacology and Toxicology, School of Medicine
    ABCG2 is a member of the ATP-binding cassette transporter superfamily, and its overexpression causes multidrug resistance (MDR) in cancer chemotherapy. ABCG2 may also protect cancer stem cells by extruding cytotoxic materials. ABCG2 has previously been shown to exist as a high-order homo-oligomer consisting of possibly 8-12 subunits, and the oligomerization domain was mapped to the C-terminal domain, including TM5, ECL3, and TM6. In this study, we further investigate this domain in detail for the role of each segment in the oligomerization and drug transport function of ABCG2 using domain swapping and site-directed mutagenesis. We found that none of the three segments (TM5, TM6, and ECL3) is essential for the oligomerization activity of ABCG2 and that any one of these three segments in the full-length context is sufficient to support ABCG2 oligomerization. While TM5 plays an important role in the drug transport function of ABCG2, TM6 and ECL3 are replaceable. Thus, each segment in the TM5-ECL3-TM6 domain plays a distinctive role in the oligomerization and function of ABCG2.
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    The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis
    (Springer, 2024) Colbert, Brett M.; Lanting, Cris; Smeal, Molly; Blanton, Susan; Dykxhoorn, Derek M.; Tang, Pei-Ciao; Getchell, Richard L.; Velde, Hedwig; Fehrmann, Mirthe; Thorpe, Ryan; Chapagain, Prem; Elkhaligy, Heidy; Kremer, Hannie; Yntema, Helger; Haer-Wigman, Lonneke; Redfield, Shelby; Sun, Tieqi; Bruijn, Saskia; Plomp, Astrid; Goderie, Thadé; van de Kamp, Jiddeke; Free, Rolien H.; Wassink-Ruiter, Jolien Klein; Widdershoven, Josine; Vanhoutte, Els; Rotteveel, Liselotte; Kriek, Marjolein; van Dooren, Marieke; Hoefsloot, Lies; de Gier, Heriette H. W.; DOOFNL Consortium; Schaefer, Amanda; Kolbe, Diana; Azaiez, Hela; Rabie, Grace; Aburayyan, Armal; Kawas, Mariana; Kanaan, Moien; Holder, Jourdan; Usami, Shin-Ichi; Chen, Zhengyi; Dai, Pu; Holt, Jeffrey; Nelson, Rick; Choi, Byung Yoon; Shearer, Eliot; Smith, Richard J. H.; Pennings, Ronald; Liu, Xue Zhong; Otolaryngology -- Head and Neck Surgery, School of Medicine
    TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.
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    Tumor-Infiltrating Immune-Related Long Non-Coding RNAs Indicate Prognoses and Response to PD-1 Blockade in Head and Neck Squamous Cell Carcinoma
    (Frontiers Media, 2021-10-19) Ma, Ben; Jiang, Hongyi; Luo, Yi; Liao, Tian; Xu, Weibo; Wang, Xiao; Dong, Chuanpeng; Ji, Qinghai; Wang, Yu; BioHealth Informatics, School of Informatics and Computing
    Long non-coding RNAs (lncRNAs) in immune cells play critical roles in tumor cell-immune cell interactions. This study aimed to characterize the landscape of tumor-infiltrating immune-related lncRNAs (Ti-lncRNAs) and reveal their correlations with prognoses and immunotherapy response in head and neck squamous cell carcinoma (HNSCC). We developed a computational model to identify Ti-lncRNAs in HNSCC and analyzed their associations with clinicopathological features, molecular alterations, and immunotherapy response. A signature of nine Ti-lncRNAs demonstrated an independent prognostic factor for both overall survival and disease-free survival among the cohorts from Fudan University Shanghai Cancer Center, The Cancer Genome Atlas, GSE41613, and GSE42743. The Ti-lncRNA signature scores in immune cells showed significant associations with TP53 mutation, CDKN2A mutation, and hypoxia. Inferior signature scores were enriched in patients with high levels of PDCD1 and CTLA4 and high expanded immune gene signature (IGS) scores, who displayed good response to PD-1 blockade in HNSCC. Consistently, superior clinical response emerged in melanoma patients with low signature scores undergoing anti-PD-1 therapy. Moreover, the Ti-lncRNA signature was a prognostic factor independent of PDCD1, CTLA4, and the expanded IGS score. In conclusion, tumor-infiltrating immune profiling identified a prognostic Ti-lncRNA signature indicative of clinical response to PD-1 blockade in HNSCC.