Abstract:
:The chemokine Stromal-derived factor-1alpha (SDF-1alpha) interacts with seven transmembrane (TM) G-protein-coupled receptor (GPR), CXCR4. SDF-1alpha is linked to inflammation, chemoattraction, cancer metastasis, and hematopoiesis. Tachykinin (Tac1) peptides bind seven transmembrane (TM), GPR and are involved in tumor promotion. SDF-1alpha regulates Tac1 expression in non-tumorigenic breast cells through a bimodal pattern with repression at high levels through nuclear factor-kappa B (NFkappaB) activation. This study focuses on the mechanism of activation at low SDF-1alpha 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-1alpha-mediated Tac1 activation. Western blots and functional assays with specific inhibitors indicated that SDF-1alpha phosphorylated CREB (P-CREB) via Galpha(i)2-PI3K-protein kinase C (PKC)zeta-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-1alpha. This finding is significant, since Tac1 is relevant to breast cancer metastasis, to bone marrow where stromal cells have a significant facilitating function.
journal_name
J Mol Endocrinoljournal_title
Journal of molecular endocrinologyauthors
Corcoran KE,Malhotra A,Molina CA,Rameshwar Pdoi
10.1677/JME-07-0111subject
Has Abstractpub_date
2008-03-01 00:00:00pages
113-23issue
3eissn
0952-5041issn
1479-6813pii
40/3/113journal_volume
40pub_type
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