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Calcium homeostasis is correlated closely with the occurrence and development of various cancers. The role of calcium homeostasis in prostate cancer has remained unclear. The present study aimed to investigate the relationship between transmembrane and crimp-crimp domain 1 (TMCO1) and calreticulin (CALR) in the pathological characteristics of prostate cancer and the mechanism of action on prostate cancer metastasis. Effects of CALR recombinant protein and TMCO1 knockdown on prostate cancer cells were investigated using following methods: cell cloning, Transwell, wound scratch assay, JC-1 assay, Fluo-4 Assay, endoplasmic reticulum (ER) fluorescent probe, mitochondrial fluorescence probe, Western blot and Immunofluorescence. TMCO1 and CALR are overexpressed in prostate cancer and knockdown of TMCO1 significantly inhibited the invasion, migration and cell proliferation. Furthermore, knocking down TMCO1 modulated the intensity of ER probes and mitochondrial fluorescence probes, and affected the levels of intracellular calcium ion and mitochondrial membrane potential. In addition, CALR recombinant protein upregulated the expression of epithelial-mesenchymal transition marker, Vimentin, Conversely, knockout of TMCO1 significantly reduced the expression of CALR and Vimentin. Knockout of TMCO1 can reverse the effect of CALR recombinant protein, elucidating the pivotal roles of TMCO1 and CALR in the regulation of prostate cancer metastasis through modulation of calcium homeostasis.

Background and purpose: Transmembrane and coiled-coil domains 1 (TMCO1) is a recently discovered endoplasmic reticulum calcium channel protein that has been found to be associated with the progression of various tumors, however, its role in cervical cancer has not yet been clarified. This study aimed to investigate the effects of TMCO1 on the proliferation and migration of cervical cancer HeLa cells. Methods: By transfecting cervical cancer HeLa cells with plasmids, cells with stable overexpression of TMCO1 and cells with stable knockdown of TMCO1 were obtained. Cell counting kit-8 (CCK-8) assay, clone formation assay and EdU labeling assay were used to detect cell proliferation ability, transwell assay was used to detect cell migration ability, and proteomic analysis was performed on the cells that stably overexpressed TMCO1 and control cells. Results: TThe CCK-8 experiment and clone formation experiment showed that overexpression of TMCO1 in cervical cancer HeLa cells significantly increased their proliferation ability (P

Abstract Background Maintaining homeostasis of Ca2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca2+ signaling and key cellular functions. Although Ca2+ depletion has been known to cause ER stress which in turn activates the unfolded protein response (UPR), how UPR sensors/transducers respond to excess Ca2+ when ER stores are overloaded remain largely unclear. Results Here, we report for the first time that overloading of ER Ca2+ can directly sensitize the IRE1α-XBP1 axis. The overloaded ER Ca2+ in TMCO1-deficient cells can cause BiP dissociation from IRE1α, promote the dimerization and stability of the IRE1α protein, and boost IRE1α activation. Intriguingly, attenuation of the over-activated IRE1α-XBP1s signaling by a IRE1α inhibitor can cause a significant cell death in TMCO1-deficient cells. Conclusions Our data establish a causal link between excess Ca2+ in ER stores and the selective activation of IRE1α-XBP1 axis, underscoring an unexpected role of overload of ER Ca2+ in IRE1α activation and in preventing cell death.

Background: Maintaining homeostasis of Ca2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca2+ signaling and key cellular functions. Although Ca2+ depletion has been known to cause ER stress which in turn activates the unfolded protein response (UPR), how UPR sensors/transducers respond to excess Ca2+ when ER stores are overloaded remain largely unclear. Results: Here, we report for the first time that overloading of ER Ca2+ can directly sensitize the IRE1α-XBP1 axis. The overloaded ER Ca2+ in TMCO1-deficient cells can cause BiP dissociation from IRE1α, promote the dimerization and stability of the IRE1α protein, and boost IRE1α activation. Intriguingly, attenuation of the over-activated IRE1α-XBP1s signaling by a IRE1α inhibitor can cause a significant cell death in TMCO1-deficient cells. Conclusions: Our data establish a causal link between excess Ca2+ in ER stores and the selective activation of IRE1α-XBP1 axis, underscoring an unexpected role of overload of ER Ca2+ in IRE1α activation and in preventing cell death. [ABSTRACT FROM AUTHOR]

Ca2+ release from the endoplasmic reticulum (ER) is an essential event in the modulation of Ca2+ homeostasis, which is coordinated by multiple biological processes, ranging from cell proliferation to apoptosis. Deregulated Ca2+ homeostasis is linked with various cancer hallmarks; thus, uncovering the mechanisms underlying Ca2+ homeostasis dynamics may lead to new anticancer treatment strategies. Here, we demonstrate that a reported Ca2+-channel protein TMCO1 (transmembrane and coiled-coil domains 1) is overexpressed in colon cancer tissues at protein levels but not at messenger RNA levels in colon cancer. Further study revealed that TMCO1 is a substrate of ER-associated degradation E3 ligase Gp78. Intriguingly, Gp78-mediated TMCO1 degradation at K186 is under the control of the iASPP (inhibitor of apoptosis-stimulating protein of p53) oncogene. Mechanistically, iASPP robustly reduces ER Ca2+ stores, mainly by competitively binding with Gp78 and interfering with Gp78-mediated TMCO1 degradation. A positive correlation between iASPP and TMCO1 proteins is further validated in human colon tissues. Inhibition of iASPP-TMCO1 axis promotes cytosolic Ca2+ overload-induced apoptotic cell death, reducing tumor growth both in vitro and in vivo. Thus, iASPP-TMCO1 represents a promising anticancer treatment target by modulating Ca2+ homeostasis. [ABSTRACT FROM AUTHOR]

Transmembrane and Coiled-Coil Domains 1 (TMCO1) protein is encoded by TMCO1 gene consists of 7 exons. Previous studies have identified multiple TMCO1 variants in patients with cerebro-facio-thoracic dysplasia (CFTD) and TMCO1 locus was also shown to be associated with primary open angle glaucoma (POAG). However, there are limited number of research exist reporting associations of the TMCO1 gene sequence variants and majority of the findings affirm the pathogenicity of the nonsense and frameshift TMCO1 variants and their associations with clinical phenotypes. Thus functional properties of the single nucleotide variants causing amino acid changes in the TMCO1 are yet to be comprehensively elucidated. In this study, we evaluated the effects of amino acid substitutions on protein structure, identified their putative roles in post-translational modifications (PTM) and in regulatory mechanism for TMCO1 protein. We classified 41 missense variants as pathogenic based on combined scores of common in silico tools (SIFT, MutationTaster2, Polyphen2). Of these 41 variants, four (p.K211Q, p.K105E, p.S235F, p.K237R) were identified to be located in PTMs and regulatory protein binding sites; thus they were proposed to be putative functional variants. Moreover, rs1387528611 (p.Lys128Gln) had also strong evidence (RegulomeDB score=2b) for its possible regulatory function. The results of our in silico analyses highlight the functional importance of the missense TMCO1 variants that may contribute to the TMCO1-associated disease phenotypes and further in vivo evaluation yet to be needed to uncover their role in human diseases.

A decade has passed since transmembrane coiled-coil domains 1 (TMCO1) defect syndrome was identified in 11 undiagnosed patients within the Old Order Amish of Northeastern Ohio—a disorder characterized by a distinctive craniofacial dysmorphism, skeletal anomalies and global developmental delay. Twenty seven patients, from diverse ethnic groups, have been reported with pathogenic TMCO1 variants now recognized to cause cerebrofaciothoracic dysplasia (CFTD). The implication of previously uncharacterized TMCO1 within disease has instigated a 10-year journey to understand the function of TMCO1 protein in Ca2+ homeostasis. TMCO1 is an ER Ca2+ leak channel which facilitates Ca2+ leak upon ER “overload” through the novel Ca2+ load activated Ca2+ mechanism. This mini-review brings together the clinical and scientific advances made since the discovery of TMCO1 deficiency in disease, including broadened phenotype, understanding of pathophysiology, and implications to patient management of TMCO1 defect syndrome.

A decade has passed since transmembrane coiled-coil domains 1 (TMCO1) defect syndrome was identified in 11 undiagnosed patients within the Old Order Amish of Northeastern Ohio—a disorder characterized by a distinctive craniofacial dysmorphism, skeletal anomalies and global developmental delay. Twenty seven patients, from diverse ethnic groups, have been reported with pathogenic TMCO1 variants now recognized to cause cerebrofaciothoracic dysplasia (CFTD). The implication of previously uncharacterized TMCO1 within disease has instigated a 10-year journey to understand the function of TMCO1 protein in Ca2+ homeostasis. TMCO1 is an ER Ca2+ leak channel which facilitates Ca2+ leak upon ER "overload" through the novel Ca2+ load activated Ca2+ mechanism. This mini-review brings together the clinical and scientific advances made since the discovery of TMCO1 deficiency in disease, including broadened phenotype, understanding of pathophysiology, and implications to patient management of TMCO1 defect syndrome. [ABSTRACT FROM AUTHOR]

To investigate the association of known candidate genes with the visual field (VF) progression of primary open angle glaucoma (POAG) in a Han Chinese population. We included 440 POAG patients in this study. Fourteen previously reported single nucleotide polymorphisms (SNPs) at five different gene regions (TGFBR3-CDC7, TMCO1, CDKN2B-AS1, ATOH7, and SIX1/SIX6) were genotyped. Age at diagnosis, gender, intraocular pressure (IOP), mean defect (MD) of VF, vertical cup disk ratio (VCDR), best corrected visual acuity (BCVA), central corneal thickness (CCT), and axial length (AL) were recorded at baseline. Patients were followed up for 5 years to evaluate VF progression over time. Clinical information and allele frequencies of 14 SNPs were compared between patients who progressed and who did not within 5 years by multivariate logistic regression. Survival analysis was performed to evaluate the contribution of the associated SNP by cox regression. Greater MD (P < 0.0001), increased VCDR (P = 0.0001), higher IOP (P = 0.0003), worse BCVA (P = 0.002), and older age (P = 0.030) at the baseline were associated with VF progression. Both multivariate logistic regression and cox regression survival analysis showed none of the 14 SNPs statistically associated with VF progression adjusted with age at diagnosis, gender, baseline MD, follow-up IOP, CCT, and AL. There were lack of association of SNPs at TGFBR3-CDC7, TMCO1, ATOH7, CDKN2B-AS1, SIX1/SIX6 loci with VF progression in POAG patients in Han Chinese. Further studies are needed to evaluate the association of genetic variants with VF progression.

To investigate the association of known candidate genes with the visual field (VF) progression of primary open angle glaucoma (POAG) in a Han Chinese population. We included 440 POAG patients in this study. Fourteen previously reported single nucleotide polymorphisms (SNPs) at five different gene regions (TGFBR3-CDC7 , TMCO1 , CDKN2B-AS1 , ATOH7 , and SIX1/SIX6) were genotyped. Age at diagnosis, gender, intraocular pressure (IOP), mean defect (MD) of VF, vertical cup disk ratio (VCDR), best corrected visual acuity (BCVA), central corneal thickness (CCT), and axial length (AL) were recorded at baseline. Patients were followed up for 5 years to evaluate VF progression over time. Clinical information and allele frequencies of 14 SNPs were compared between patients who progressed and who did not within 5 years by multivariate logistic regression. Survival analysis was performed to evaluate the contribution of the associated SNP by cox regression. Greater MD (P < 0.0001), increased VCDR (P = 0.0001), higher IOP (P = 0.0003), worse BCVA (P = 0.002), and older age (P = 0.030) at the baseline were associated with VF progression. Both multivariate logistic regression and cox regression survival analysis showed none of the 14 SNPs statistically associated with VF progression adjusted with age at diagnosis, gender, baseline MD, follow-up IOP, CCT, and AL. There were lack of association of SNPs at TGFBR3-CDC7 , TMCO1 , ATOH7 , CDKN2B-AS1 , SIX1/SIX6 loci with VF progression in POAG patients in Han Chinese. Further studies are needed to evaluate the association of genetic variants with VF progression. [ABSTRACT FROM AUTHOR]

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1; OMIM# 213980) is a rare autosomal recessive disorder characterized by the clinical triad of developmental delay and/or intellectual disability, a typical facial gestalt with brachycephaly, highly-arched bushy eyebrows, synophrys, hypertelorism, wide nasal bridge, and short nose, as well as multiple vertebrae and rib malformations, such as bifid and fused ribs and abnormal vertebral segmentation and fusion. Biallelic loss-of-function variants in TMCO1 cause CFSMR1. We report on two unrelated Egyptian patients with a phenotype suggestive of CFSMR. Single whole-exome sequencing in patient 1 and Sanger sequencing of TMCO1 in patient 2 revealed the same homozygous TMCO1 nonsense variant c.187C > T/p.(Arg63*) in both affected individuals; patients' healthy parents were heterozygous carriers of the variant. Congenital hearing loss in patients 1 and 2 is an occasional finding in individuals affected by CFSMR. Camptodactyly and syndactyly, which were noted in patient 2, have not or rarely been reported in CFSMR. Review of the literature revealed a total of 30 individuals with the clinically recognizable and unique phenotype of CFSMR1, including the patients reported here, who all carried biallelic TMCO1 variants. Six different TMCO1 variants have been reported in the 30 patients from 14 families, comprising three nonsense, two 2-bp deletions, and a splice donor site variant. All disease-associated TMCO1 variants likely represent null alleles resulting in absence of the encoded protein. TMCO1 has been proposed to act as a Ca2+ channel, while other data revealed TMCO1 as a mitochondrial protein and a component of the translocon at the endoplasmic reticulum, a cellular machinery important for the biogenesis of multi-pass membrane proteins. RAB5IF / C20orf2 4 has recently been identified as causative gene for craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-2 (CFSMR2; OMIM# 616994). Heterodimerization of RAB5IF/C20orf24 and TMCO1 and their interdependence may suggest a pathophysiological role of ER-mitochondria interaction underlying CFSMR. [ABSTRACT FROM AUTHOR]