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Amantha Thathiah

Publications and source records attributed to Amantha Thathiah.

7 recordsLinked to original sources
PubMed2026

A complete genome for the common marmoset.

The common marmoset is a New World monkey widely used to study primate evolution and human disease. We present a telomere-to-telomere (T2T) reference assembly for the species, plus three near-T2T haplotypes. These resolve previously inaccessible regions, including the centromeres, sex chromosomes, subterminal satellites, acrocentric chromosomes, and the major histocompatibility complex (MHC). We find marmoset centromeres carry dimeric alpha satellites with chromosomal specificity, flanked by inactive layers interpreted as ancestral centromere remnants. We assemble gene-poor, satellite-rich short arms of the acrocentrics and find that most can harbor rDNA and all share pseudo-homolog regions (PHRs). PHR-sharing chromosomes also share closely related centromeric satellites, consistent with a model of ongoing rDNA-facilitated recombinational exchange between heterologous chromosomes. We further identify over 500 marmoset-lineage-specific transcribed genes with previously unknown transcript models or expansions. These resources, along with a preliminary pangenome, improve the utility of the marmoset as a model organism and address gaps in primate genome evolution.

Animals↗
PubMed2004

MT1-MMP mediates MUC1 shedding independent of TACE/ADAM17.

MUC1, a transmembrane mucin, plays a critical role in embryo implantation, protection of mucosal epithelia from microbial and enzymic attack and various aspects of tumour progression. In some species, a decrease in uterine epithelial MUC1 protein and mRNA expression accompanies embryo implantation. In other species, such as rabbits and humans, MUC1 appears to be locally removed at blastocyst attachment sites, suggesting the action of a protease. We previously demonstrated that MUC1 is proteolytically released from the surface of a human uterine epithelial cell line, HES, and identified TACE/ADAM17 (where TACE stands for tumour necrosis factor-alpha converting enzyme and ADAM for A Disintegrin And Metalloprotease-like) as a constitutive and PMA-stimulated MUC1 sheddase [Thathiah, Blobel and Carson (2003) J. Biol. Chem. 274, 3386-3394]. Further characterization of the proteolytic activity(ies) mediating MUC1 release indicates that MUC1 shedding is also accelerated by the tyrosine phosphatase inhibitor pervanadate. Pervanadate, but not PMA, stimulates MUC1 shedding in TACE-deficient cells, indicating activation of a metalloproteolytic activity(ies) distinct from TACE. Pervanadate-stimulated MUC1 release is inhibited by the TIMP-2 (tissue inhibitor of metalloprotease-2) and TIMP-3, but is unaffected by TIMP-1, consistent with the MT-MMPs (membrane-type matrix metalloproteases). Pervanadate stimulation of MUC1 shedding is absent from MUC1-transfected MT1-MMP-deficient fibroblasts, but is restored after MUC1 and MT1-MMP co-transfection. Furthermore, overexpression of MT1-MMP in HES cells enhances pervanadate-stimulated MUC1 release, and MT1-MMP co-localizes with MUC1 in vivo at the apical surface of receptive-phase human uterine epithelia. Taken together, these studies characterize a MUC1 sheddase activity in addition to TACE and identify MT1-MMP as a pervanadate-stimulated MUC1 sheddase.

ADAM Proteins↗
PubMed2004

Tumor necrosis factor alpha stimulates MUC1 synthesis and ectodomain release in a human uterine epithelial cell line.

Regulation of MUC1 expression and removal is a salient feature of embryo implantation, bacterial clearance, and tumor progression. In some species, embryo implantation is accompanied by a transcriptional decline in uterine epithelial expression of MUC1. In other species, MUC1 is locally removed at blastocyst attachment sites, suggesting a proteolytic activity. Previously, we demonstrated that MUC1 is proteolytically released from the surface of a human uterine epithelial cell line, HES, and identified TNFalpha converting enzyme/a disintegrin and metalloprotease 17 as a constitutive and phorbol ester-stimulated MUC1 sheddase. The aims of the current study were to test the ability of soluble factors elevated during the periimplantation interval in vivo to stimulate ectodomain shedding of MUC1 from HES uterine epithelial cells and to characterize the nature of this proteolytic activity(ies). We identified TNFalpha as a prospective endogenous stimulus of MUC1 ectodomain release and of MUC1 and TNFalpha converting enzyme/a disintegrin and metalloprotease 17 expression. Moreover, we established that TNFalpha-stimulated MUC1 shedding occurs independently of increased de novo protein synthesis and demonstrated that the TNFalpha-induced increase in MUC1 gene expression is mediated through the kappaB site in the MUC1 promoter. Finally, we determined that the TNFalpha-sensitive MUC1 sheddase is inhibited by the metalloprotease inhibitor, TNFalpha protease inhibitor (TAPI), and the endogenous tissue inhibitor of metalloprotease-3. Collectively, these studies provide the initial in vitro characterization of a putative physiological stimulus of MUC1 ectodomain release and establish the nature of the metalloproteolytic activity(ies) involved.

Antigens, Surface↗
PubMed2004

MUC1: a multifunctional cell surface component of reproductive tissue epithelia.

MUC1 is a large, transmembrane mucin glycoprotein expressed at the apical surface of a variety of reproductive tract epithelia. Functions attributed to MUC1 include those generally associated with mucins such as lubrication and hydration of cell surfaces as well as protection from microorganisms and degradative enzymes. In addition, MUC1 is an effective inhibitor of both cell-cell and cell-extracellular matrix interactions in both normal and malignant contexts. Moreover, a series of recent studies has shown that the highly conserved cytoplasmic tail of MUC1 interacts specifically with a series of important signal transducing molecules including beta-catenin, Grb2 and erbB family members. MUC1 expression in normal epithelia can be quite dynamic, varying in response to steroid hormone or cytokine influences. Following malignant transformation, MUC1 often becomes highly overexpressed, loses its apical restriction, and displays aberrant glycosylation and altered mRNA splice variants. Regulation of MUC1 expression can occur at the transcriptional level. In addition, post-translational regulation of cell surface expression occurs via the activity of cell surface proteases or "sheddases" that release soluble forms of the large ectodomains. This review will briefly summarize studies of MUC1 expression and function in reproductive tissues with particular emphasis on the uterus. In addition, current knowledge of the mechanisms of MUC1 gene regulation, metabolic processing and potential signal transducing functions will be presented.

Animals↗
PubMed2002

Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 shedding.

MUC1 clearance from the uterine epithelial cell surface is a prerequisite for the creation of an environment conducive to embryo implantation. In some species, reduced mRNA levels along with metabolic turnover account for loss of MUC1 during the receptive phase throughout the uterine epithelium. In other species, MUC1 is rapidly lost solely at the site of blastocyst attachment, suggesting the action of a protease. Correlative studies also indicate the presence of soluble forms of MUC1 in cell culture supernatants in vitro and in bodily fluids in vivo. To characterize the proteolytic activity mediating MUC1 release, shedding of MUC1 was analyzed in a human uterine epithelial cell line (HES) that abundantly expresses and readily sheds MUC1. MUC1 release was stimulated by phorbol 12-myristate 13-acetate and was markedly inhibited by the synthetic peptide hydroxamate metalloprotease inhibitor, tumor necrosis factor-alpha protease inhibitor (TAPI), as well as by an endogenous inhibitor of matrix metalloproteases, tissue inhibitor of metalloproteases (TIMP)-3. These characteristics along with studies conducted with cell lines genetically deficient in various ADAMs (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (TACE)/ADAM 17 as a MUC1 sheddase. Furthermore, both TACE and MUC1 were expressed in human uterine epithelia during the receptive phase, and co-immunoprecipitation experiments revealed a physical interaction between TACE and MUC1 in HES cells. These studies establish a proteolytic mechanism for MUC1 clearance from a human uterine epithelial cell line and identify TACE as a MUC1 sheddase.

ADAM Proteins↗
PubMed2002

Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening.

High density cDNA microarray screening was used to determine changes in gene expression occurring during the transition between the early luteal (prereceptive) and mid-luteal (receptive) phases in human endometrium. Of approximately 12,000 genes profiled, 693 (5.8%) displayed >2-fold differences in relative levels of expression between these stages. Of these, 370 genes (3.1%) displayed decreases ranging from 2- to >100-fold while 323 genes (2.7%) displayed increases ranging from 2- to >45-fold. Many genes correspond to mRNAs encoding proteins previously shown to change in a similar manner between the proliferative and mid-luteal phases, serving as one validation of the microarray screening results. In addition, novel genes were identified. Genes encoding cell surface receptors, adhesion and extracellular matrix proteins and growth factors accounted for 20% of the changes. Several genes were studied further by Northern blot analyses. These results confirmed that claudin-4/Clostridium perfringens enterotoxin (CPE) receptor and osteopontin (OPN) mRNA increased approximately 4- and 12-fold respectively, while betaig-H3 (BIGH3) decreased >80% during the early to mid-luteal transition. Immunostaining also revealed strong specific staining for claudin-4/CPE, EP(1) and prostaglandin receptor in epithelia, and leukotriene B4 receptor in both epithelia and stroma, at the mid-luteal stage. Collectively, these studies identify multiple new candidate markers that may be used to predict the receptive phase in humans. Some of these gene products, e.g. OPN, may play direct roles in embryo-uterine interactions during the implantation process.

Blotting, Northern↗