Stromal-derived factor-1α induces a non-canonical pathway to activate the endocrine-linked Tac1 gene in non-tumorigenic breast cells

Kelly E. Corcoran, Ashwani Malhotra, Carlos Molina, Pranela Rameshwar

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Abstract

The chemokine Stromal-derived factor-1α (SDF-1α) interacts with seven transmembrane (TM) G-protein-coupled receptor (GPR), CXCR4. SDF-1α is linked to inflammation, chemoattraction, cancer metastasis, and hematopoiesis. Tachykinin (Tac1) peptides bind seven transmembranel (TM), GPR and are involved in tumor promotion. SDF-1α regulates Tac1 expression in non-tumorigenic breast cells through a bimodal pattern with repression at high levels through nuclear factor-kappa B (NFΚB) activation. This study focuses on the mechanism of activation at low SDF-1α in MCF12A non-tumorigenic breast cells. Reporter gene assays with the 5′ flanking region of Tac1 (exon 1 omitted) and co-transfection with the repressor of cAMP response element (CREB) (ICER), and transfection with the CRE sites mutated, verified critical roles for CRE sites in SDF-1α-mediated Tac1 activation. Western blots and functional assays with specific inhibitors indicated that SDF-1α phosphorylated CREB (P-CREB) via Gα2-PI3K-protein kinase C (PKC)ζ-p38-extracellular signal-regulated kinase (ERK) and no evidence of cAMP-PKA pathway. This observation is different from previous studies that reported CREB-phosphorylated PKA pathway in the activation of Tac1 in bone marrow stromal cells. This suggests cell specificity in Tac1 expression. In conclusion, this study reports on a non-canonical pathway in Tac1 activation by SDF-1α. This finding is significant, since Tac1 is relevant to breast cancer metastasis, to bone marrow where stromal cells have a significant facilitating function.

Original languageEnglish
Pages (from-to)113-123
Number of pages11
JournalJournal of Molecular Endocrinology
Volume40
Issue number3-4
DOIs
StatePublished - 1 Mar 2008

Fingerprint

Breast
Mesenchymal Stromal Cells
Transfection
Neoplasm Metastasis
Genes
Tachykinins
NF-kappa B
5' Flanking Region
Extracellular Signal-Regulated MAP Kinases
Hematopoiesis
Response Elements
G-Protein-Coupled Receptors
Phosphatidylinositol 3-Kinases
Reporter Genes
Chemokines
Protein Kinase C
Exons
Neoplasms
Western Blotting
Breast Neoplasms

Cite this

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title = "Stromal-derived factor-1α induces a non-canonical pathway to activate the endocrine-linked Tac1 gene in non-tumorigenic breast cells",
abstract = "The chemokine Stromal-derived factor-1α (SDF-1α) interacts with seven transmembrane (TM) G-protein-coupled receptor (GPR), CXCR4. SDF-1α is linked to inflammation, chemoattraction, cancer metastasis, and hematopoiesis. Tachykinin (Tac1) peptides bind seven transmembranel (TM), GPR and are involved in tumor promotion. SDF-1α regulates Tac1 expression in non-tumorigenic breast cells through a bimodal pattern with repression at high levels through nuclear factor-kappa B (NFΚB) activation. This study focuses on the mechanism of activation at low SDF-1α in MCF12A non-tumorigenic breast cells. Reporter gene assays with the 5′ flanking region of Tac1 (exon 1 omitted) and co-transfection with the repressor of cAMP response element (CREB) (ICER), and transfection with the CRE sites mutated, verified critical roles for CRE sites in SDF-1α-mediated Tac1 activation. Western blots and functional assays with specific inhibitors indicated that SDF-1α phosphorylated CREB (P-CREB) via Gα2-PI3K-protein kinase C (PKC)ζ-p38-extracellular signal-regulated kinase (ERK) and no evidence of cAMP-PKA pathway. This observation is different from previous studies that reported CREB-phosphorylated PKA pathway in the activation of Tac1 in bone marrow stromal cells. This suggests cell specificity in Tac1 expression. In conclusion, this study reports on a non-canonical pathway in Tac1 activation by SDF-1α. This finding is significant, since Tac1 is relevant to breast cancer metastasis, to bone marrow where stromal cells have a significant facilitating function.",
author = "Corcoran, {Kelly E.} and Ashwani Malhotra and Carlos Molina and Pranela Rameshwar",
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Stromal-derived factor-1α induces a non-canonical pathway to activate the endocrine-linked Tac1 gene in non-tumorigenic breast cells. / Corcoran, Kelly E.; Malhotra, Ashwani; Molina, Carlos; Rameshwar, Pranela.

In: Journal of Molecular Endocrinology, Vol. 40, No. 3-4, 01.03.2008, p. 113-123.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Stromal-derived factor-1α induces a non-canonical pathway to activate the endocrine-linked Tac1 gene in non-tumorigenic breast cells

AU - Corcoran, Kelly E.

AU - Malhotra, Ashwani

AU - Molina, Carlos

AU - Rameshwar, Pranela

PY - 2008/3/1

Y1 - 2008/3/1

N2 - The chemokine Stromal-derived factor-1α (SDF-1α) interacts with seven transmembrane (TM) G-protein-coupled receptor (GPR), CXCR4. SDF-1α is linked to inflammation, chemoattraction, cancer metastasis, and hematopoiesis. Tachykinin (Tac1) peptides bind seven transmembranel (TM), GPR and are involved in tumor promotion. SDF-1α regulates Tac1 expression in non-tumorigenic breast cells through a bimodal pattern with repression at high levels through nuclear factor-kappa B (NFΚB) activation. This study focuses on the mechanism of activation at low SDF-1α in MCF12A non-tumorigenic breast cells. Reporter gene assays with the 5′ flanking region of Tac1 (exon 1 omitted) and co-transfection with the repressor of cAMP response element (CREB) (ICER), and transfection with the CRE sites mutated, verified critical roles for CRE sites in SDF-1α-mediated Tac1 activation. Western blots and functional assays with specific inhibitors indicated that SDF-1α phosphorylated CREB (P-CREB) via Gα2-PI3K-protein kinase C (PKC)ζ-p38-extracellular signal-regulated kinase (ERK) and no evidence of cAMP-PKA pathway. This observation is different from previous studies that reported CREB-phosphorylated PKA pathway in the activation of Tac1 in bone marrow stromal cells. This suggests cell specificity in Tac1 expression. In conclusion, this study reports on a non-canonical pathway in Tac1 activation by SDF-1α. This finding is significant, since Tac1 is relevant to breast cancer metastasis, to bone marrow where stromal cells have a significant facilitating function.

AB - The chemokine Stromal-derived factor-1α (SDF-1α) interacts with seven transmembrane (TM) G-protein-coupled receptor (GPR), CXCR4. SDF-1α is linked to inflammation, chemoattraction, cancer metastasis, and hematopoiesis. Tachykinin (Tac1) peptides bind seven transmembranel (TM), GPR and are involved in tumor promotion. SDF-1α regulates Tac1 expression in non-tumorigenic breast cells through a bimodal pattern with repression at high levels through nuclear factor-kappa B (NFΚB) activation. This study focuses on the mechanism of activation at low SDF-1α in MCF12A non-tumorigenic breast cells. Reporter gene assays with the 5′ flanking region of Tac1 (exon 1 omitted) and co-transfection with the repressor of cAMP response element (CREB) (ICER), and transfection with the CRE sites mutated, verified critical roles for CRE sites in SDF-1α-mediated Tac1 activation. Western blots and functional assays with specific inhibitors indicated that SDF-1α phosphorylated CREB (P-CREB) via Gα2-PI3K-protein kinase C (PKC)ζ-p38-extracellular signal-regulated kinase (ERK) and no evidence of cAMP-PKA pathway. This observation is different from previous studies that reported CREB-phosphorylated PKA pathway in the activation of Tac1 in bone marrow stromal cells. This suggests cell specificity in Tac1 expression. In conclusion, this study reports on a non-canonical pathway in Tac1 activation by SDF-1α. This finding is significant, since Tac1 is relevant to breast cancer metastasis, to bone marrow where stromal cells have a significant facilitating function.

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DO - 10.1677/JME-07-0111

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