Biology subjects

Ko, L.

Publications and source records attributed to Ko, L..

8 recordsLinked to original sources

bioRxiv2026

ADRA2B genetic polymorphism modulates vagus nerve stimulation response

Introduction. Given interest in vagus nerve stimulation (VNS) as a potential therapy for Alzheimer's disease, due to its hypothesized influence on the noradrenergic (NA) system, there is a need to understand the pronounced individual differences in responsiveness to VNS in aging. We tested whether a genetic polymorphism related to NA signaling, the {Delta}301-303 deletion in the ADRA2B receptor, modulates transcutaneous auricular (taVNS) effects on task-related pupillary responses or pupil-linked cortical activity in noradrenergic projection territory. Methods. Forty-one adults (61% deletion carriers; ages 19-79) performed a visual oddball task during a sham-controlled single-blind crossover taVNS trial. Of these people, 25 (68% deletion carriers) also performed the same task with simultaneous fMRI. Results. ADRA2B genotype predicted the taVNS effect on oddball pupillary responses (t(37) = 3.03, p = .004, d = 0.84). Deletion carrier responses were more likely to increase, while non-carrier responses decreased. Carriers showed stronger spatial alignment between pupil-BOLD coupling and cortical norepinephrine transporter (NET) expression (t(22) = 2.82, p = .010, adjusted d = 1.21). This difference was selective to NET among 19 PET maps (all other p > .11). The individual effect of taVNS predicted NET alignment of pupil-BOLD coupling ({rho} = .45, p = .023). Conclusions. ADRA2B {Delta}301-303 deletion status, which is thought to increase NA availability, predicts the direction of the pupillary response to taVNS and how tightly pupil-linked BOLD activity aligns with cortical noradrenergic projection territory.

neuroscience↗

bioRxiv2025

Interactions Between Dietary Metabolites and Regulatory Risk Variants for Human Colon Cancer

Interactions between genetic variants and environmental factors influence malignancy risk, including for colorectal cancer (CRC). Prevalent CRC susceptibility loci reside predominantly in noncoding regulatory DNA where they may interact with dietary influences to dysregulate expression of specific genes predisposing to neoplasia. The impacts of CRC protective and risk dietary metabolites, butyrate and deoxycholic acid, were thus studied on the transcription-directing activity of 3703 regulatory CRC-associated variants via massively parallel reporter assays (MPRA) in human colonic cells. 1595 variant-dietary metabolite interactions were identified, pointing to dysregulation of MED13L, NKD2, and several modulators of Wnt/{beta}-catenin signaling in potential CRC gene-environment interactions (GxE). Opposing impacts of butyrate and deoxycholic acid were also uncovered, indicating dietary influences may converge on common CRC risk loci and nominating FOSL1 and SP1 as mediators of these opposing responses. Coupling MPRA to relevant environmental factors offers an approach to extend insight into GxE in common human cancers.

genomics↗

bioRxiv2025

The Adhesion GPCR ADGRL2 engages Gα13 to Enable Epidermal Differentiation

Homeostasis relies on signaling networks controlled by cell membrane receptors. Although G-protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors, their specific roles in the epidermis are not fully understood. Dual CRISPR-Flow and single cell Perturb-seq knockout screens of all epidermal GPCRs were thus performed, uncovering an essential requirement for adhesion GPCR ADGRL2 (latrophilin 2) in epidermal differentiation. Among potential downstream guanine nucleotide-binding G proteins, ADGRL2 selectively activated G13. Perturb-seq of epidermal G proteins and follow-up tissue knockouts verified that G13 is also required for epidermal differentiation. A cryo-electron microscopy (cryo-EM) structure in lipid nanodiscs showed that ADGRL2 engages with G13 at multiple interfaces, including via a novel interaction between ADGRL2 intracellular loop 3 (ICL3) and a G13-specific QQQ glutamine triplet sequence in its GTPase domain. In situ gene mutation of this interface sequence impaired epidermal differentiation, highlighting an essential new role for an ADGRL2-G13 axis in epidermal differentiation.

cell biology↗

bioRxiv2024

Disease-Linked Regulatory DNA Variants and Homeostatic Transcription Factors in Epidermis

Identifying noncoding single nucleotide variants (SNVs) in regulatory DNA linked to polygenic disease risk, the transcription factors (TFs) they bind, and the target genes they dysregulate is a goal in polygenic disease research. Massively parallel reporter gene analysis (MPRA) of 3,451 SNVs linked to risk for polygenic skin diseases characterized by disrupted epidermal homeostasis identified 355 differentially active SNVs (daSNVs). daSNV target gene analysis, combined with daSNV editing, underscored dysregulated epidermal differentiation as a pathomechanism shared across common polygenic skin diseases. CRISPR knockout screens of 1772 human TFs revealed 108 TFs essential for epidermal progenitor differentiation, uncovering novel roles for ZNF217, CXXC1, FOXJ2, IRX2 and NRF1. Population sampling CUT&RUN of 27 homeostatic TFs identified allele-specific DNA binding (ASB) differences at daSNVs enriched near epidermal homeostasis and monogenic skin disease genes, with notable representation of SP/KLF and AP-1/2 TFs. This resource implicates dysregulated differentiation in risk for diverse polygenic skin diseases.

genetics↗

bioRxiv2019

Mutant GT198 in angiogenesis as a common origin of human prostate and bladder cancers

Prostate and bladder cancers are common cancers in men. It has been speculated that the high concomitant incidence of the two cancers is due to a potential shared cause underlying both cancers. In this report, we have identified a common cause of human prostate and bladder cancers as the mutant oncoprotein GT198 (PSMC3IP). GT198 is a DNA repair factor and a steroid hormone receptor coactivator. GT198 has been previously shown to be mutated in angiogenic pericyte stem cells in solid tumor microenvironment. GT198 is also a direct protein target of chemo drugs paclitaxel and doxorubicin. Here we show, the GT198 gene is mutated with protein overexpression in tumor stroma of human prostate and bladder cancers. Affected stromal cells include angiogenic blood vessel pericyte stem cells, and vascular smooth muscle cell lineages including myofibroblasts in prostate and smooth muscle cells in bladder. In prostate cancers, GT198+ tumor stromal cells are associated with early stages of cancer with lower Gleason scores. In bladder cancers, the presence of angiogenesis and GT198+ stroma are associated with better progression-free survival in docetaxel-treated patients. Together, our evidence suggests that angiogenic pericyte stem cells are initial lesions producing a mutant stroma carrying GT198 somatic mutations. Subsequently, mutant myofibroblasts promote adenocarcinomas in prostate and mutant smooth muscle cells promote urothelial carcinomas in bladder. Chemo drugs targeting to GT198 is more effective in early stages of cancers with GT198+ stromal cells. This study supports oncoprotein GT198 as a common cause and a drug target in human prostate and bladder cancers.

pathology↗

bioRxiv2019

Oncoprotein GT198 Vaccination Delays Tumor Growth in MMTV-PyMT Mice

Different effects of anticancer drugs between mouse and human have caused increasing concerns. A better understanding of cancer initiation between the two species is needed. We have previously identified an oncoprotein GT198 (PSMC3IP) in human breast cancer. In this report, we investigated GT198 in MMTV-PyMT mouse mammary gland tumors and found a reconcilable mechanism in human and mouse. Specifically, distinct tumor initiating stimuli in human and mouse result in a common GT198-mediated tumorigenic pathway in both species. Here we show, similar to human breast cancer even before a tumor appears, GT198 has overexpressed in mouse tumor stroma including pericyte stem cells, descendent adipocytes, fibroblasts, and myoepithelial cells. Using recombinant GT198 protein as an antigen, we vaccinated MMTV-PyMT mice and found that the GT198 vaccine delayed mouse tumor growth and reduced lung metastasis. The antitumor effects in vaccinated mice were linearly correlated with serum titers of GT198 antibody, which can recognize cell surface GT198 protein on viable tumor cells confirmed by FACS. Furthermore, tumor cells isolated from MMTV-PyMT mice were re-implanted into normal FVB/N mice, GT198+ tumor cells induced faster tumor growths than GT198- tumor cells. Together, this first study of GT198 vaccine in mouse showed its effectiveness in antitumor and anti-metastasis. The finding may accelerate future development of GT198 immunotherapy in human cancer. Our finding also indicates that even though distinct cancer-initiation stimuli exist between mouse and human, a common tumorigenic pathway mediated by oncoprotein GT198 is shared in both species.

cancer biology↗

bioRxiv2019

Oncoprotein GT198 is a direct target of taxol

Taxol (paclitaxel) is one of the most successful chemotherapeutic drugs in the treatment of human cancer. It has recently been questioned whether the mechanism of action in mitotic arrest, which is ubiquitously present in all cells, is sufficient to explain the tumor specificity, clinical efficacy, and side effects of taxol. In this report, we have identified a new protein target of taxol as GT198 (gene symbol PSMC3IP, also known as Hop2). GT198 is an oncoprotein and a DNA repair factor involved in human common solid tumors. The GT198 gene carries germline mutations in breast and ovarian cancer families and recurrent somatic mutations in tumor microenvironment. Mutant GT198 was identified in pericyte stem cells on capillary blood vessels inducing tumor angiogenesis. GT198 is a DNA-binding protein dimer, also stimulates DNA repair, regulates meiosis, participates in homologous DNA recombination, and activates nuclear receptor-mediated gene expression. Here we show that taxol directly binds to the DNA-binding domain of GT198 in vitro. Taxol serves as an allosteric inhibitor to block DNA binding to GT198 with an IC50 of 8.6 nM. Labeled taxol colocalizes with GT198 in interphase nuclei of cultured cells. Decreased GT198 expression desensitizes taxolinduced cell death, and taxol inhibits GT198 nuclear foci formation during DNA repair. Together, these results demonstrate that GT198 is a previously unrecognized direct protein target of taxol. The finding of taxol target as an oncoprotein GT198 in common solid tumors provides a rationale for the clinical efficacy of taxol. We anticipate that GT198 may serve as a clinical predictive marker of taxol efficacy as well as a new drug target for future anti-cancer therapy.

pharmacology and toxicology↗

bioRxiv2019

Oncoprotein CoAA repeats interact with RNA polymerase II CTD repeats

The heptad repeating sequence of the C-terminal domain (CTD) of the largest subunit of RNA polymerase II is highly conserved in eukaryotes. In yeast, a CTD code consisting of pairs of heptad repeats is essential for viability. However, the strict requirement of diheptad repeats for the CTD function in transcription and splicing is unexplained. Here we show that CoAA (gene symbol RBM14), an oncoprotein and mammalian transcriptional coactivator, possesses diheptad repeats and directly interacts with the CTD. CoAA comprises 27 copies of tyrosine-rich repeats and regulates pre-mRNA synthesis and alternative splicing. Tyrosine substitutions in either the CoAA repeats or the CTD repeats diminish their interactions. Ser2- or Ser5-phosphorylated CTD peptides exhibit higher binding affinity to CoAA than the corresponding non-phosphorylated CTD peptide. CoAA dynamically interacts with both the CTD and hnRNP M, which is an alternative splicing regulator also comprising diheptad repeats. Arginine methylation of CoAA switches its interaction from the hnRNP M repeats to the CTD repeats. This study provides a mechanism for CoAA at the interface of transcription and alternative splicing, and explains the functional requirement of diheptad repeats in the CTD. In the human genome, tyrosine-rich repeats similar to the CoAA repeats were only found in six oncoproteins including EWS and SYT. We suggest that the diheptad sequence is one of the signature features for the CTD interaction among oncoproteins involved in transcription and alternative splicing. We anticipate that direct RNA Pol II interaction is a mechanism in oncogenesis.

biochemistry↗