Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo-and a Cys–His domain

Karlsson, Olof; Thor, Stefan; Norberg, Torbjörn; Ohlsson, Helena; Edlund, Thomas

doi:10.1038/344879a0

Cited by 654 publications

(418 citation statements)

References 18 publications

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“…A ZNF185 cDNA encoding 452 amino-acid (a.a.) residues with a single C-terminallocated LIM domain was assembled based on the sequence of an expressed sequence tagged (EST) clone and a genomic DNA sequence (Heiss et al, 1997). The LIM domain is a cysteine-and histidine-rich double zinc-finger motif named after the three-homeodomain proteins: Lin-l 1, Isl-1 and Mec-3 (Way and Chalfie, 1988;Freyd et al, 1990;Karlsson et al, 1990). This domain is present in a wide range of proteins whose functions include many fundamental biological processes such as cell lineage specification, cytoskeleton organization and organ development (Dawid et al, 1998;Bach, 2000;Kadrmas and Beckerle, 2004).…”

Section: Introductionmentioning

confidence: 99%

ZNF185, an actin–cytoskeleton-associated growth inhibitory LIM protein in prostate cancer

2006

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We have recently identified ZNF185 as a gene that is downregulated in prostate cancer (PCa), in part via epigenetic alteration, and maybe associated with disease progression. In this study, we cloned the ZNF185 cDNA from normal human prostate tissues and investigated its biological function. We show that ZNF185 is a novel actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein that localizes to F-actin structures, and is enriched at focal adhesions. We find that the NH 2 -terminal region, which we designate the actintargeting domain, facilitates ZNF185 binding to actin in vitro and is both necessary and sufficient to mediate actin-cytoskeleton targeting of ZNF185, whereas the LIM domain, which is localized in the COOH-terminus is dispensable for this phenomenon. Interestingly, ectopic expression of full-length ZNF185, but not a mutant lacking the actin-targeting domain, could suppress proliferation and anchorage-independent growth of PCa cells. Together, our data suggest that ZNF185 may function as a tumor-suppressor protein by associating with the actincytoskeleton.

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Section: Introductionmentioning

confidence: 99%

ZNF185, an actin–cytoskeleton-associated growth inhibitory LIM protein in prostate cancer

2006

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“…1 This transcription factor possesses two N-terminal LIM domains and one C-terminal homeodomain. 2 LIM domains (named after their discovery in the proteins Lin 11, ISL1 and Mec-3) are protein structural domains that mediate protein-protein interactions critical to cellular processes and have a role in the regulation of the cytoskeleton, organogenesis and oncogenesis.…”

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confidence: 99%

ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin

et al. 2013

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The human insulin gene enhancer-binding protein islet-1 (ISL1) is a transcription factor involved in the differentiation of the neuroendocrine pancreatic cells. Recent studies identified ISL1 as a marker for pancreatic well-differentiated neuroendocrine neoplasms. However, little is known about ISL1 expression in pancreatic poorly differentiated and in extrapancreatic well and poorly differentiated neuroendocrine neoplasms. We studied the immunohistochemical expression of ISL1 in 124 neuroendocrine neoplasms. Among pancreatic neuroendocrine neoplasms, 12/13 with poor differentiation were negative, whereas 5/7 with good differentiation but a Ki67 420% were positive. In extrapancreatic neuroendocrine neoplasms, strong positivity was found in Merkel cell carcinomas (25/25), pulmonary small cell neuroendocrine carcinomas (21/23), medullary thyroid carcinomas (9/9), paragangliomas/pheochromocytomas (6/6), adrenal neuroblastomas (8/8) and head and neck neuroendocrine carcinomas (4/5), whereas no or only weak staining was recorded in pulmonary carcinoids (3/15), olfactory neuroblastomas (1/4) and basaloid head and neck squamous cell carcinomas (0/15). ISL1 stained the neuroendocrine carcinoma component of 5/8 composite carcinomas and also normal neuroendocrine cells in the thyroid, adrenal medulla, stomach and colorectum. Poorly differentiated neuroendocrine neoplasms, regardless of their ISL1 expression, were usually TP53 positive. Our results show the almost ubiquitous expression of ISL1 in extrapancreatic poorly differentiated neuroendocrine neoplasms and neuroblastic malignancies and its common loss in pancreatic poorly differentiated neuroendocrine neoplasms. These findings modify the role of ISL1 as a marker for pancreatic neuroendocrine neoplasms and suggest that ISL1 has a broader involvement in differentiation and growth of neuroendocrine neoplasms than has so far been assumed. 995 www.modernpathology.org differentiation in mouse experiments. 8 Apart from its role in the cell line development of the endocrine pancreas, ISL1 was found to have a major role as a marker of cardiac progenitor cell lineage. 9 Recently, ISL1 expression was studied in welldifferentiated pancreatic neuroendocrine neoplasms that are labeled by the WHO as neuroendocrine tumors (NETs). 10,11 In these neoplasms, ISL1 proved to be a good marker for pancreatic NETs and their metastases, with a specificity of 78.4-100% and a sensitivity of 74.3-77.8%. [10][11][12] Neuroendocrine carcinomas of pancreatic and extrapancreatic origin so far have not or only occasionally been tested for ISL1 expression. 12-15 Following our own observation of a strong ISL1 reactivity in a case of a widely metastatic small cell neuroendocrine carcinoma of unknown origin, we launched this study with the aim to test the reliability of ISL1 as a marker for distinguishing pancreatic neuroendocrine carcinomas from their extrapancreatic counterparts and mimics. In addition, we also studied some well-differentiated extrapancreatic neuroendocrine neoplasms such as thyroid ...

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“…In brief, the LIM motif is a 'helix-loop-helix' domain that was originally identified in three developmentally regulated transcription factors, Caenorhabditis elegans Lin-11, rat Isl-1, and C. elegans Mec-3 (Freyd et al, 1990;Karlsson et al, 1990), but has since been identified in a variety of proteins. The LIM domain consists of a 52 amino-acid sequence CX 2 CX 16 -23 HX 2 CX 2 CX 2 CX 16 -21 CX 2 -3 (C/H/D) motif, which typically has been associated with DNA-binding homeodomains and kinase domains (Freyd et al, 1990;Karlsson et al, 1990;Dawid et al, 1995Dawid et al, , 1998.…”

Section: Discussionmentioning

confidence: 99%

“…The LIM domain consists of a 52 amino-acid sequence CX 2 CX 16 -23 HX 2 CX 2 CX 2 CX 16 -21 CX 2 -3 (C/H/D) motif, which typically has been associated with DNA-binding homeodomains and kinase domains (Freyd et al, 1990;Karlsson et al, 1990;Dawid et al, 1995Dawid et al, , 1998. The LIM domain has been recognised as a distinct protein motif within LIM homeodomain proteins by both genetic and biochemical methods (Freyd et al, 1990;Karlsson et al, 1990;Way and Chalfie, 1994). The LIM domain has been found to mediate 'protein -protein' interactions of cytoplasmic and nuclear proteins.…”

Section: Discussionmentioning

confidence: 99%

A novel IL-10 signalling mechanism regulates TIMP-1 expression in human prostate tumour cells

Wang

Stearns

2003

Br J Cancer

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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 (B74 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.

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Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo-and a Cys–His domain

Cited by 654 publications

References 18 publications

ZNF185, an actin–cytoskeleton-associated growth inhibitory LIM protein in prostate cancer

ZNF185, an actin–cytoskeleton-associated growth inhibitory LIM protein in prostate cancer

ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin

A novel IL-10 signalling mechanism regulates TIMP-1 expression in human prostate tumour cells

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