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Placing ion channels into a signaling network of T cells: from maturing thymocytes to healthy T lymphocytes or leukemic T lymphoblasts.

Dobrovinskaya O, Delgado-Enciso I, Quintero-Castro LJ, Best-Aguilera C, Rojas-Sotelo RM, Pottosin I - Biomed Res Int (2015)

Bottom Line: A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially.In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death.In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Research, University of Colima, 28045 Colima, COL, Mexico.

ABSTRACT
T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility.

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Related in: MedlinePlus

Ca2+-dependent signaling pathways in T-ALL. Ca2+ influx may occur through CRAC channels, activated in receptor-dependent manner: (a) muscarinic receptors (M1–M5) are stimulated by Ach produced by leukemic cells themselves, but mechanisms of elevated Ach production are not studied yet; (b) TCR or preTCR receptors are activated through mechanisms which may engage Notch upregulation. Another mechanism for Ca2+ influx involves activation of nonselective Ca2+-permeable channels, activated by different mechanisms. Driving force for sustained Ca2+ influx is generated by K+ efflux through selective K+ channels. Most important genetic lesions and signaling pathways are indicated, together with percentages for each type of lesion recognized in clinical cases. For more details, see the text.
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fig2: Ca2+-dependent signaling pathways in T-ALL. Ca2+ influx may occur through CRAC channels, activated in receptor-dependent manner: (a) muscarinic receptors (M1–M5) are stimulated by Ach produced by leukemic cells themselves, but mechanisms of elevated Ach production are not studied yet; (b) TCR or preTCR receptors are activated through mechanisms which may engage Notch upregulation. Another mechanism for Ca2+ influx involves activation of nonselective Ca2+-permeable channels, activated by different mechanisms. Driving force for sustained Ca2+ influx is generated by K+ efflux through selective K+ channels. Most important genetic lesions and signaling pathways are indicated, together with percentages for each type of lesion recognized in clinical cases. For more details, see the text.

Mentions: Aberrant Notch1 activation in T-ALL is suggested to promote deregulated proliferation and prevent apoptosis. Molecular mechanism of Notch-mediated cell-cycle progression was shown to involve activation of c-myc [36, 42], NFAT [43, 44], and AKT/PI3K pathway and inhibition of PTEN expression [45] (Figure 2). Among the targets, activated by the Notch1 in the T-ALL, transcriptional factors HES1, HERPI 1&2, and EGF-containing fibulin—like extracellular matrix protein 1 (EFEMP1), vascular endothelial growth factor VEGF, inhibitor of DNA binding 1 (ID1), and SnoRNAs of the box H/ACA quantitative accumulation (SHQ1), immune associated nucleotide 4 like 1 IAN4L1/GIMAP5, and coreceptor CD28 were also reported [46, 47]. Notch1 upregulation enhances the G1/S transition through the induction of Skp2 expression; Skp2 is the component of E-3 ligase complex that degrades p27Kip1 and p21Cip1, inhibitors of cyclin-CDK2/4 complexes [48]. NF-κB cascade seems also to be activated by the Notch1 upregulation, and attenuation of NF-κB resulted in T-ALL suppression, both in vivo and in vitro [49]. Inhibition of apoptosis may occur through Notch1 activation of different pathways, including the NF-κB or the PKB/AKT/mTOR ones, leading to the p53 inhibition [25].


Placing ion channels into a signaling network of T cells: from maturing thymocytes to healthy T lymphocytes or leukemic T lymphoblasts.

Dobrovinskaya O, Delgado-Enciso I, Quintero-Castro LJ, Best-Aguilera C, Rojas-Sotelo RM, Pottosin I - Biomed Res Int (2015)

Ca2+-dependent signaling pathways in T-ALL. Ca2+ influx may occur through CRAC channels, activated in receptor-dependent manner: (a) muscarinic receptors (M1–M5) are stimulated by Ach produced by leukemic cells themselves, but mechanisms of elevated Ach production are not studied yet; (b) TCR or preTCR receptors are activated through mechanisms which may engage Notch upregulation. Another mechanism for Ca2+ influx involves activation of nonselective Ca2+-permeable channels, activated by different mechanisms. Driving force for sustained Ca2+ influx is generated by K+ efflux through selective K+ channels. Most important genetic lesions and signaling pathways are indicated, together with percentages for each type of lesion recognized in clinical cases. For more details, see the text.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383400&req=5

fig2: Ca2+-dependent signaling pathways in T-ALL. Ca2+ influx may occur through CRAC channels, activated in receptor-dependent manner: (a) muscarinic receptors (M1–M5) are stimulated by Ach produced by leukemic cells themselves, but mechanisms of elevated Ach production are not studied yet; (b) TCR or preTCR receptors are activated through mechanisms which may engage Notch upregulation. Another mechanism for Ca2+ influx involves activation of nonselective Ca2+-permeable channels, activated by different mechanisms. Driving force for sustained Ca2+ influx is generated by K+ efflux through selective K+ channels. Most important genetic lesions and signaling pathways are indicated, together with percentages for each type of lesion recognized in clinical cases. For more details, see the text.
Mentions: Aberrant Notch1 activation in T-ALL is suggested to promote deregulated proliferation and prevent apoptosis. Molecular mechanism of Notch-mediated cell-cycle progression was shown to involve activation of c-myc [36, 42], NFAT [43, 44], and AKT/PI3K pathway and inhibition of PTEN expression [45] (Figure 2). Among the targets, activated by the Notch1 in the T-ALL, transcriptional factors HES1, HERPI 1&2, and EGF-containing fibulin—like extracellular matrix protein 1 (EFEMP1), vascular endothelial growth factor VEGF, inhibitor of DNA binding 1 (ID1), and SnoRNAs of the box H/ACA quantitative accumulation (SHQ1), immune associated nucleotide 4 like 1 IAN4L1/GIMAP5, and coreceptor CD28 were also reported [46, 47]. Notch1 upregulation enhances the G1/S transition through the induction of Skp2 expression; Skp2 is the component of E-3 ligase complex that degrades p27Kip1 and p21Cip1, inhibitors of cyclin-CDK2/4 complexes [48]. NF-κB cascade seems also to be activated by the Notch1 upregulation, and attenuation of NF-κB resulted in T-ALL suppression, both in vivo and in vitro [49]. Inhibition of apoptosis may occur through Notch1 activation of different pathways, including the NF-κB or the PKB/AKT/mTOR ones, leading to the p53 inhibition [25].

Bottom Line: A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially.In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death.In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Research, University of Colima, 28045 Colima, COL, Mexico.

ABSTRACT
T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting "leukemogenic" signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility.

Show MeSH
Related in: MedlinePlus