Human MRCKα is regulated by cellular iron levels and interferes with transferrin iron uptake

Čmejla, Radek; Ptáčková, Pavlína; Petrák, Jir̆ı́; Savvulidi, Filipp; Černý, Jan; Šebesta, Ondřej; Vyoral, Daniel

doi:10.1016/j.bbrc.2010.02.148

Cited by 19 publications

(13 citation statements)

References 16 publications

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“…Even considering this finding, chromosomal gain appears not to be the only mechanism for the upregulation of CD71 expression, since SLMT-1 cells that lack chromosomal gain at the 3q region also exhibit a drastic induction of CD71 (25). It is plausible that SLMT-1 cells might be subjected to post-transcriptional regulation as a number of microRNA binding sites can be found in the 2.5 kb (NM_003234.2: 2567-5241) 3' untranslated region of CD71 mRNA (36)(37)(38). Alternatively, other epigenetic mechanisms such as promoter demethylation may also take part in the regulation of CD71 expression.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma

et al. 2014

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Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in endemic Asian regions. In the present study, we investigated the clinical implication and role of transferrin receptor CD71 in ESCC. CD71 has a physiological role in cellular iron intake and is implicated in the carcinogenesis of various types of tumors. In our cohort, more than a 2-fold upregulation of the CD71 transcript was detected in 61.5% of patients using quantitative polymerase chain reaction. Immunohistochemical analysis also showed strong membranous and cytoplasmic localization of CD71 in paraffin-embedded tumors. Staining parallel tumor sections with the proliferative marker Ki-67 revealed that the pattern of Ki-67 staining was associated with CD71 expression. Analysis of clinicopathological data indicated that CD71 overexpression can be used as an indicator for advanced T4 stage (p=0.0307). These data suggested a strong link between CD71 and ESCC. Subsequent in vitro assays using short interfering RNA (siRNA) to suppress CD71 expression confirmed the tumorigenic properties of CD71 in ESCC; cell growth inhibition and cell cycle arrest at S phase were observed in CD71-suppressed cells. The underlying mechanism involved activation of the MEK/ERK pathway. In summary, the present study provides evidence showing the tumorigenic properties of CD71 in ESCC with clinical correlations and suggests targeting CD71 as a strategy for the treatment of ESCC.

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Section: Discussionmentioning

confidence: 99%

Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma

et al. 2014

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“…1A). Recent studies have demonstrated that the internalization of the Tf-containing endosome via the cytoskeleton is under control of intracellular iron levels (6,7). In part, this uptake mechanism is mediated by myotonic dystrophy kinase-related Cdc42-binding kinase alpha (MRCKα) (6).…”

Section: Cellular Iron Metabolism and Transportmentioning

confidence: 99%

“…This molecule plays a role in organizing the actin cytoskeleton and is up-regulated by irondepletion through the iron regulatory protein (IRP)-iron-responsive element (IRE) interaction (see below) (6). MRCKα colocalizes with Tf-TfR1 complexes following their internalization and it has been shown that attenuation of MRCKα expression causes a significant decrease in Tf-mediated iron uptake (7). Additionally, it is known that Sec15l1, which is involved in the mammalian exocyst complex (8), plays a role in iron uptake from Tf via its role in exocytosis (9,10).…”

Section: Cellular Iron Metabolism and Transportmentioning

confidence: 99%

Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol

Richardson

Lane

Becker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

439

383

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The mitochondrion is well known for its key role in energy transduction. However, it is less well appreciated that it is also a focal point of iron metabolism. Iron is needed not only for heme and iron sulfur cluster (ISC)-containing proteins involved in electron transport and oxidative phosphorylation, but also for a wide variety of cytoplasmic and nuclear functions, including DNA synthesis. The mitochondrial pathways involved in the generation of both heme and ISCs have been characterized to some extent. However, little is known concerning the regulation of iron uptake by the mitochondrion and how this is coordinated with iron metabolism in the cytosol and other organelles (e.g., lysosomes). In this article, we discuss the burgeoning field of mitochondrial iron metabolism and trafficking that has recently been stimulated by the discovery of proteins involved in mitochondrial iron storage (mitochondrial ferritin) and transport (mitoferrin-1 and -2). In addition, recent work examining mitochondrial diseases (e.g., Friedreich's ataxia) has established that communication exists between iron metabolism in the mitochondrion and the cytosol. This finding has revealed the ability of the mitochondrion to modulate whole-cell ironprocessing to satisfy its own requirements for the crucial processes of heme and ISC synthesis. Knowledge of mitochondrial ironprocessing pathways and the interaction between organelles and the cytosol could revolutionize the investigation of iron metabolism.iron sulfur cluster | heme | Friedreich's ataxia | frataxin | sideroblastic anemia

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“…28 Internalization of the Tf-Tfr1 complex in endosomes is under control of intracellular iron levels and can be regulated. 29,30 Absorption of iron from the intestinal lining or its release is controlled by hepcidin, a small peptide produced in the liver, that acts as the ligand for FPN1. 31,32 Binding of hepcidin to FPN1 at membrane of intestinal enterocytes and macrophages causes the internalization of FPN1 and its degradation resulting in reduced release of iron into body fluids [33][34][35] (Figure 2(a)).…”

Section: Iron Homeostasismentioning

confidence: 99%

Overdosing on iron: Elevated iron and degenerative brain disorders

D’Mello¹,

Kindy

2020

Exp Biol Med (Maywood)

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All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

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Human MRCKα is regulated by cellular iron levels and interferes with transferrin iron uptake

Cited by 19 publications

References 16 publications

Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma

Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma

Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol

Overdosing on iron: Elevated iron and degenerative brain disorders

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