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RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation.

Sparvero LJ, Asafu-Adjei D, Kang R, Tang D, Amin N, Im J, Rutledge R, Lin B, Amoscato AA, Zeh HJ, Lotze MT - J Transl Med (2009)

Bottom Line: The Receptor for Advanced Glycation Endproducts [RAGE] is an evolutionarily recent member of the immunoglobulin super-family, encoded in the Class III region of the major histocompatability complex.Activation and upregulation of RAGE by its ligands leads to enhanced survival.RAGE and its isoforms sit in a pivotal role, regulating metabolism, inflammation, and epithelial survival in the setting of stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Surgery and Bioengineering, University of Pittsburgh Cancer Institute, Pittsburgh, USA. sparverolj@upmc.edu

ABSTRACT
The Receptor for Advanced Glycation Endproducts [RAGE] is an evolutionarily recent member of the immunoglobulin super-family, encoded in the Class III region of the major histocompatability complex. RAGE is highly expressed only in the lung at readily measurable levels but increases quickly at sites of inflammation, largely on inflammatory and epithelial cells. It is found either as a membrane-bound or soluble protein that is markedly upregulated by stress in epithelial cells, thereby regulating their metabolism and enhancing their central barrier functionality. Activation and upregulation of RAGE by its ligands leads to enhanced survival. Perpetual signaling through RAGE-induced survival pathways in the setting of limited nutrients or oxygenation results in enhanced autophagy, diminished apoptosis, and (with ATP depletion) necrosis. This results in chronic inflammation and in many instances is the setting in which epithelial malignancies arise. RAGE and its isoforms sit in a pivotal role, regulating metabolism, inflammation, and epithelial survival in the setting of stress. Understanding the molecular structure and function of it and its ligands in the setting of inflammation is critically important in understanding the role of this receptor in tumor biology.

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RAGE is Central to Many Fundamental Biological Processes. Focusing on RAGE allows us to view many aspects of disordered cell biology and associated chronic diseases. Chronic stress promotes a broad spectrum of maladies through RAGE expression and signaling, focusing the host inflammatory and reparative response.
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Figure 1: RAGE is Central to Many Fundamental Biological Processes. Focusing on RAGE allows us to view many aspects of disordered cell biology and associated chronic diseases. Chronic stress promotes a broad spectrum of maladies through RAGE expression and signaling, focusing the host inflammatory and reparative response.

Mentions: RAGE is expressed as both full-length, membrane-bound forms (fl-RAGE or mRAGE, not to be confused with mouse RAGE) and various soluble forms lacking the transmembrane domain. Soluble RAGE is produced by both proteolytic cleavage of fl-RAGE and alternative mRNA splicing. The soluble isoforms include the extracellular domains but lack the transmembrane and cytoplasmic domains [12-15]. Soluble RAGE derived specifically from proteolytic cleavage is sRAGE, although this terminology is not consistent in the literature – sRAGE sometimes refers to soluble RAGE in general. RAGE is expressed at low levels in a wide range of differentiated adult cells in a regulated manner but in mature lung type-I pneumocytes it is expressed at substantially higher levels than in other resting cell types. It is highly expressed in readily detectable amounts in embryonic cells [16]. RAGE is also highly expressed and associated with many inflammation-related pathological states such as vascular disease, cancer, neurodegeneration and diabetes (Figure 1) [17,18]. The exceptions are lung tumors and idiopathic pulmonary fibrosis, in which RAGE expression decreases from a higher level in healthy tissue [19,20].


RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation.

Sparvero LJ, Asafu-Adjei D, Kang R, Tang D, Amin N, Im J, Rutledge R, Lin B, Amoscato AA, Zeh HJ, Lotze MT - J Transl Med (2009)

RAGE is Central to Many Fundamental Biological Processes. Focusing on RAGE allows us to view many aspects of disordered cell biology and associated chronic diseases. Chronic stress promotes a broad spectrum of maladies through RAGE expression and signaling, focusing the host inflammatory and reparative response.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2666642&req=5

Figure 1: RAGE is Central to Many Fundamental Biological Processes. Focusing on RAGE allows us to view many aspects of disordered cell biology and associated chronic diseases. Chronic stress promotes a broad spectrum of maladies through RAGE expression and signaling, focusing the host inflammatory and reparative response.
Mentions: RAGE is expressed as both full-length, membrane-bound forms (fl-RAGE or mRAGE, not to be confused with mouse RAGE) and various soluble forms lacking the transmembrane domain. Soluble RAGE is produced by both proteolytic cleavage of fl-RAGE and alternative mRNA splicing. The soluble isoforms include the extracellular domains but lack the transmembrane and cytoplasmic domains [12-15]. Soluble RAGE derived specifically from proteolytic cleavage is sRAGE, although this terminology is not consistent in the literature – sRAGE sometimes refers to soluble RAGE in general. RAGE is expressed at low levels in a wide range of differentiated adult cells in a regulated manner but in mature lung type-I pneumocytes it is expressed at substantially higher levels than in other resting cell types. It is highly expressed in readily detectable amounts in embryonic cells [16]. RAGE is also highly expressed and associated with many inflammation-related pathological states such as vascular disease, cancer, neurodegeneration and diabetes (Figure 1) [17,18]. The exceptions are lung tumors and idiopathic pulmonary fibrosis, in which RAGE expression decreases from a higher level in healthy tissue [19,20].

Bottom Line: The Receptor for Advanced Glycation Endproducts [RAGE] is an evolutionarily recent member of the immunoglobulin super-family, encoded in the Class III region of the major histocompatability complex.Activation and upregulation of RAGE by its ligands leads to enhanced survival.RAGE and its isoforms sit in a pivotal role, regulating metabolism, inflammation, and epithelial survival in the setting of stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Surgery and Bioengineering, University of Pittsburgh Cancer Institute, Pittsburgh, USA. sparverolj@upmc.edu

ABSTRACT
The Receptor for Advanced Glycation Endproducts [RAGE] is an evolutionarily recent member of the immunoglobulin super-family, encoded in the Class III region of the major histocompatability complex. RAGE is highly expressed only in the lung at readily measurable levels but increases quickly at sites of inflammation, largely on inflammatory and epithelial cells. It is found either as a membrane-bound or soluble protein that is markedly upregulated by stress in epithelial cells, thereby regulating their metabolism and enhancing their central barrier functionality. Activation and upregulation of RAGE by its ligands leads to enhanced survival. Perpetual signaling through RAGE-induced survival pathways in the setting of limited nutrients or oxygenation results in enhanced autophagy, diminished apoptosis, and (with ATP depletion) necrosis. This results in chronic inflammation and in many instances is the setting in which epithelial malignancies arise. RAGE and its isoforms sit in a pivotal role, regulating metabolism, inflammation, and epithelial survival in the setting of stress. Understanding the molecular structure and function of it and its ligands in the setting of inflammation is critically important in understanding the role of this receptor in tumor biology.

Show MeSH
Related in: MedlinePlus