Cubilin, the Intrinsic Factor-Vitamin B12 Receptor in Development and Disease

2020 ◽  
Vol 27 (19) ◽  
pp. 3123-3150 ◽  
Author(s):  
Renata Kozyraki ◽  
Olivier Cases
Keyword(s):  
Vitamin B12 ◽  
Cancer Progression ◽  
Intrinsic Factor ◽  
Basic Research ◽  
Toxic Substances ◽  
Human Pathology ◽  
Peripheral Membrane Protein ◽  
Epidermal Growth ◽  
Fgf8 Signaling

Gp280/Intrinsic factor-vitamin B12 receptor/Cubilin (CUBN) is a large endocytic receptor serving multiple functions in vitamin B12 homeostasis, renal reabsorption of protein or toxic substances including albumin, vitamin D-binding protein or cadmium. Cubilin is a peripheral membrane protein consisting of 8 Epidermal Growth Factor (EGF)-like repeats and 27 CUB (defined as Complement C1r/C1s, Uegf, BMP1) domains. This structurally unique protein interacts with at least two molecular partners, Amnionless (AMN) and Lrp2/Megalin. AMN is involved in appropriate plasma membrane transport of Cubilin whereas Lrp2 is essential for efficient internalization of Cubilin and its ligands. Observations gleaned from animal models with Cubn deficiency or human diseases demonstrate the importance of this protein. In this review addressed to basic research and medical scientists, we summarize currently available data on Cubilin and its implication in renal and intestinal biology. We also discuss the role of Cubilin as a modulator of Fgf8 signaling during embryonic development and propose that the Cubilin-Fgf8 interaction may be relevant in human pathology, including in cancer progression, heart or neural tube defects. We finally provide experimental elements suggesting that some aspects of Cubilin physiology might be relevant in drug design.

scholarly journals The Role of Canonical Wnt Signaling in Regulating Radioresistance

2018 ◽  
Vol 48 (2) ◽  
pp. 419-432 ◽  
Author(s):  
Yuanyuan Zhao ◽  
Leilei Tao ◽  
Jun Yi ◽  
Haizhu Song ◽  
Longbang Chen
Keyword(s):  
Wnt Signaling ◽  
Cancer Progression ◽  
Wnt Signaling Pathway ◽  
Growth Factor Receptor ◽  
Cancer Resistance ◽  
Canonical Wnt Signaling ◽  
Damage Repair ◽  
Epidermal Growth ◽  
Canonical Wnt

Radioresistance is a major obstacle in radiotherapy for cancer, and strategies are needed to overcome this problem. Currently, radiotherapy combined with targeted therapy such as inhibitors of phosphoinosotide 3-kinase/Akt and epidermal growth factor receptor signaling have become the focus of studies on radiosensitization. Apart from these two signaling pathways, which promote radioresistance, deregulation of Wnt signaling is also associated with the radioresistance of multiple cancers. Wnts, as important messengers in the tumor microenvironment, are involved in cancer progression mainly via canonical Wnt signaling. Their role in promoting DNA damage repair and inhibiting apoptosis facilitates cancer resistance to radiation. Thus, it seems reasonable to target Wnt signaling as a method for overcoming radioresistance. Many small-molecule inhibitors that target the Wnt signaling pathway have been identified and shown to promote radiosensitization. Therefore, a Wnt signaling inhibitor may help to overcome radioresistance in cancer therapy.

Genetic polymorphisms of EGF 5'-UTR in patients with glioma: A possible predictive marker of outcome.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13009-e13009
Author(s):  
Emanuela Vattemi ◽  
Giovanna Cipollini ◽  
Cristina Dealis ◽  
Lorena Rossi ◽  
Susanne Baier ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Direct Sequencing ◽  
Predictive Marker ◽  
Reference Sequence ◽  
Published Data ◽  
Sequencing Method ◽  
Number Of Patients ◽  
Predictive Role ◽  
Epidermal Growth

e13009 Background: Epidermal growth factor (EGF) plays an important role in carcinogenesis. An adenine (A) to guanine (G) single nucleotide polymorphism at position 61 in the 5'-untranslated region (5'-UTR) of the EGF gene has been found to be associated with levels of EGF production and contribute to the risk of glioma. However, published data are contradictory. EGF +61G/A polymorphism may contribute to the risk of glioma in different ethnic group. Patients with glioma and GG genotype have been reported to have a risk of poorer otucome than patients with AA genotype. Purpose of this study is to investigate the potential role of this polymorphism in cancer progression and its role as predictive marker of outcome in glioma caucasian patients. Methods: EGF 61A/G polymorphism (rs4444903) was analyzed in glioma patients and was determined by means of Polymerase Chain Reaction and Direct Sequencing method (GenBank reference sequence-accession no. AC005509) from blood samples. Association of this genetic polymorphism with clinical and pathological data of patients was evaluated. Results: We investigated EGF +61G/A polymorphism in 24 glioma patients . EGF +61G allele has been found in 67% of glioma patients (25% G/G genotype and 42% A/G genotype). In astrocytomas, EGF +61G allele represents a 83% frequency; in glioblastomas and in oligodendrogliomas, EGF +61G allele frequency represents respectively 71% and 50%. In WHO IV gliomas, the EGF +61G allele represents a 63% frequency, (27% G/G and 36% A/G ), in WHO III gliomas a 77% frequency (33% G/G and 44% A/G ) and in WHO II gliomas a 50% frequency (100% A/G ). Median PFS of glioblastoma patients was 9 months. 83% of glioblastoma patients with a relapsing disease showed the G/G and A/G genotype. No difference was detected in the others histotypes. Conclusions: Our data conferm previous studies which reported G allele as a risk factor for glioma in Caucasian. G/A and G/G genotypes seem to be more rappresentative in high grade gliomas . Despite limited number of patients, our study supports the predictive role of EGF 61 A/G polymorphism in GBM. Additional large studies are warranted to confirm the role of EGF polymorphism as indipendent prognostic factor in glioma.

Role of (Glu → Arg, Q5R) mutation of the intrinsic factor in pernicious anemia and other causes of low vitamin B12

2008 ◽  
Vol 87 (7) ◽  
pp. 599-600 ◽  
Author(s):  
A. F. Remacha ◽  
E. Del Río ◽  
M. P. Sardà ◽  
C. Canals ◽  
M. Simó ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Pernicious Anemia ◽  
Intrinsic Factor

scholarly journals Role of N-acetyltransferase 2 gene polymorphism in the human pathology

2021 ◽  
Vol 6 (5) ◽  
pp. 30-43
Author(s):  
N. P. Peretolchina ◽  
I. V. Malov ◽  
I. Zh. Seminskiy
Keyword(s):  
Gene Polymorphism ◽  
Risk Groups ◽  
Human Organism ◽  
Second Phase ◽  
Toxic Substances ◽  
Drug Induced ◽  
Cancer Pathogenesis ◽  
Human Pathology ◽  
Household Chemicals

Nowadays multiple heterogeneous chemicals affect the human body. They include drugs, household chemicals, dyes, food supplements and others. The human organism can modify, inactivate, and eliminate the chemicals by biotransformation enzymes. But it is well known that biotransformation can lead to toxification phenomenon. Individuals differ from each other by the rate of chemical modification that promotes accumulation of toxins and carcinogens in some patients. An N-acetyltransferase 2 enzyme participates in the aromatic amines second phase metabolism. This work reviews the acetyltransferase gene polymorphism possible role in diseases development including drug-induced organs damage.Gene of acetyltransferase has polymorphisms associated with two haplotypes of  fast and slow substrate acetylation. Gene alleles combine in three genotypes: fast, intermediate, and slow acetylators. Acetylation rate plays a significant role in side effects development during tuberculosis treatment and cancer pathogenesis. Recently, new data described the role of enzyme in development of non-infectious diseases in the human. Scientists consider that slow acetylation genotype in combination with high xenobiotic load result in accumulation of toxic substances able to damage cells.Therefore, acetyltransferase genotyping helps to reveal risk groups of cancer and non-infectious disease development and to prescribe more effective and safe doses of drugs. 

An AKT activity threshold regulates androgen-dependent and androgen-independent PSA expression in prostate cancer cell lines

2008 ◽  
Vol 389 (6) ◽  
Author(s):  
Miltiadis Paliouras ◽  
Eleftherios P. Diamandis
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Intracellular Signaling ◽  
Specific Antigen ◽  
Independent State ◽  
Epidermal Growth ◽  
Androgen Independent

AbstractThe androgen receptor (AR) plays an important role in early prostate cancer by activating transcription of a number of genes participating in cell proliferation and growth and cancer progression. However, as the cancer progresses, prostate cancer cells transform from an androgen-dependent to an androgen-independent state. Androgen-independent prostate cancer can manifest itself in several forms, including a percentage of cancers that show reduced levels of prostate-specific antigen (PSA) and can progress without the need for the ligand or active receptor. Therefore, our goal was to examine the role of intracellular signaling pathways in an androgen-independent prostate cancerin vitromodel. Using the cell line PC3(AR)2, we stimulated cells with 5-α-dihydrotestosterone (DHT) and epidermal growth factor (EGF) and then analyzed PSA expression. We observed lower PSA expression when cells were jointly stimulated with DHT and EGF, and this was associated with an increase in AKT activity. We examined the role of AKT in AR activity and PSA expression by creating stable PC3(AR)2cell lines transfected with a PI3K-Ras-effector loop mutant. These cell lines showed lower DHT-stimulated PSA expression that correlated to changes in the phosphorylated state of AR. Therefore, we propose anin vitroandrogen-independent model in which a PI3K/AKT activity threshold and subsequent AR transactivation regulate PSA expression.

scholarly journals The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

2021 ◽  
Vol 8 ◽  
Author(s):  
Mengxi Xiu ◽  
Yongbo Wang ◽  
Baoli Li ◽  
Xifeng Wang ◽  
Fan Xiao ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Cancer Stemness ◽  
Drug Conjugates ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth

Aberrant Notch signaling profoundly affects cancer progression. Especially the Notch3 receptor was found to be dysregulated in cancer, where its expression is correlated with worse clinicopathological features and poor prognosis. The activation of Notch3 signaling is closely related to the activation of cancer stem cells (CSCs), a small subpopulation in cancer that is responsible for cancer progression. In addition, Notch3 signaling also contributes to tumor chemoresistance against several drugs, including doxorubicin, platinum, taxane, epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) and gemcitabine, through complex mechanisms. In this review, we mainly focus on discussing the molecular mechanisms by which Notch3 modulates cancer stemness and chemoresistance, as well as other cancer behaviors including metastasis and angiogenesis. What’s more, we propose potential treatment strategies to block Notch3 signaling, such as non-coding RNAs, antibodies and antibody-drug conjugates, providing a comprehensive reference for research on precise targeted cancer therapy.

Effect of Calcium on the Growth and Differentiation of Cultured Rat Esophageal Epithelial Cells

1982 ◽  
Vol 40 ◽  
pp. 132-133
Author(s):  
W.T. Gunning ◽  
M.R. Marino ◽  
M.S. Babcock ◽  
G.D. Stoner
Keyword(s):  
Epithelial Cells ◽  
Cell Types ◽  
Replication Rate ◽  
Enzymatic Dissociation ◽  
Growth Assay ◽  
Epidermal Growth ◽  
Fetal Bovine ◽  
Esophageal Epithelial Cells ◽  
Cellular Replication

The role of calcium in modulating cellular replication and differentiation has been described for various cell types. In the present study, the effects of Ca++ on the growth and differentiation of cultured rat esophageal epithelial cells was investigated.Epithelial cells were isolated from esophagi taken from 8 week-old male CDF rats by the enzymatic dissociation method of Kaighn. The cells were cultured in PFMR-4 medium supplemented with 0.25 mg/ml dialyzed fetal bovine serum, 5 ng/ml epidermal growth factor, 10-6 M hydrocortisone 10-6 M phosphoethanolamine, 10-6 M ethanolamine, 5 pg/ml insulin, 5 ng/ml transferrin, 10 ng/ml cholera toxin and 50 ng/ml garamycin at 36.5°C in a humidified atmosphere of 3% CO2 in air. At weekly intervals, the cells were subcultured with a solution containing 1% polyvinylpyrrolidone, 0.01% EGTA, and 0.05% trypsin. After various passages, the replication rate of the cells in PFMR-4 medium containing from 10-6 M to 10-3 M Ca++ was determined using a clonal growth assay.

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