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A novel IL-10 signalling mechanism regulates TIMP-1 expression in human prostate tumour cells.
- Source :
- British Journal of Cancer; 5/19/2003, Vol. 88 Issue 10, p1605-1614, 10p
- Publication Year :
- 2003
-
Abstract
- We have previously reported that interleukin 10 (IL-10) signalling stimulated activation of a specific enhancer element, termed HTE-1, to promote tissue inhibitor of matrix metalloproteinase1 (TIMP-1) expression in human bone metastatic PC-3 subclone (PC-3 ML) cells. Recently, we have identified an IL-10 responsive signal molecule, termed IL-10E1, which binds the HTE-1 element and cloned the gene encoding for the 22 kDa protein. In this paper, we have examined the mechanism of IL-10/IL-10 receptor signalling in two distinct human prostate cell lines, a 'normal' prostate epithelial cell line, termed NPTX-1532 and highly metastatic PC-3 ML tumour cells. Signalling cascade studies revealed that IL-10 stimulated tyrosine phosphorylation of JAK1 and TYK2 receptor kinases and tyrosine phosphorylation of IL-10E1. Phosphorylation, triggered IL-10E1's rapid translocation to the nucleus by 10-30 min. Deletion analysis combined with transient transfection experiments revealed that the n-terminal domain (approximately 74 a.a.) of the IL-10E1 protein, the nt-nls peptide, was stimulated by IL-10 to translocate to the nucleus and induce TIMP-1 expression. Site-directed mutagenesis further showed that phosphorylation of two tyrosine moieties (Y57 and Y62) of the nt-nls peptide was required for IL-10 activation of signalling and TIMP-1 expression. The data demonstrate, for the first time, that IL-10 receptor signalling of TIMP-1 expression is regulated by tyrosine phosphorylation of a novel gene, IL-10E1, in human prostate cells. [ABSTRACT FROM AUTHOR]
- Subjects :
- INTERLEUKIN-10
METALLOPROTEINASES
TUMOR treatment
CANCER cells
THERAPEUTICS
TYROSINE metabolism
AMINO acids
CELL receptors
CELLULAR signal transduction
COMPARATIVE studies
DOCUMENTATION
GENES
INTERLEUKINS
RESEARCH methodology
MEDICAL cooperation
PHOSPHORYLATION
PROSTATE tumors
PROTEINS
RESEARCH
RESEARCH funding
PROTEASE inhibitors
EVALUATION research
CANCER cell culture
CELL physiology
Subjects
Details
- Language :
- English
- ISSN :
- 00070920
- Volume :
- 88
- Issue :
- 10
- Database :
- Complementary Index
- Journal :
- British Journal of Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 9904401
- Full Text :
- https://doi.org/10.1038/sj.bjc.6600855