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Synergistic induction of galectin-1 by CCAAT/enhancer binding protein alpha and hypoxia-inducible factor 1alpha and its role in differentiation of acute myeloid leukemic cells.

ABSTRACT: Galectin-1 is a member of the galectin family and has a high affinity for galactose and N-acetylglucosamine moieties of glycoproteins. It mediates multiple signal transduction pathways to modulate cellular proliferation, survival, differentiation, and migration. However, the mechanisms for the regulation of its expression remain greatly elusive. We reported previously that galectin-1 is a direct target of the hypoxia-inducible factor 1 (HIF-1), a key heterodimeric transcriptional factor for the cellular response to hypoxia. Here we show that CCAAT/enhancer binding protein ? (C/EBP?), a critical transcriptional factor for hematopoietic cell differentiation, can directly activate galectin-1 through binding to the -48 to -42 bp region of its promoter. Based on the physical interaction of C/EBP? and HIF-1?, the synergistic transcriptional activity of C/EBP? and HIF-1? on the promoter of the galectin-1 gene is also found by chromatin immunoprecipitation (ChIP), ChIP followed by ChIP (ChIP-reChIP), and luciferase assay. Moreover, knockdown or chemical inhibition of galectin-1 partially blocks the differentiation induced by HIF-1? or C/EBP?, which can be rescued by recombinant galectin-1. These discoveries would shed new insights on the mechanisms for galectin-1 expression regulation and HIF-1?- and C/EBP?-induced leukemic cell differentiation.

SUBMITTER: Zhao XY

PROVIDER: S-EPMC3196150 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Synergistic induction of galectin-1 by CCAAT/enhancer binding protein alpha and hypoxia-inducible factor 1alpha and its role in differentiation of acute myeloid leukemic cells.

Zhao Xu-Yun XY Zhao Ke-Wen KW Jiang Yi Y Zhao Meng M Chen Guo-Qiang GQ

The Journal of biological chemistry 20110831 42

Galectin-1 is a member of the galectin family and has a high affinity for galactose and N-acetylglucosamine moieties of glycoproteins. It mediates multiple signal transduction pathways to modulate cellular proliferation, survival, differentiation, and migration. However, the mechanisms for the regulation of its expression remain greatly elusive. We reported previously that galectin-1 is a direct target of the hypoxia-inducible factor 1 (HIF-1), a key heterodimeric transcriptional factor for the ...[more]

PMID: 21880716

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Project description:BACKGROUND: Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1alpha and HIF-1beta/aryl hydrocarbon receptor nuclear translocator (ARNT) subunits. The prognostic relevance of HIF-1alpha protein overexpression has been shown in breast cancer. The impact of HIF-1alpha alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known. METHODS: Using real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total HIF-1alpha and 4 variants in breast tissue specimens in a series of 29 normal tissues or benign lesions (normal/benign) and 53 primary carcinomas. In breast cancers HIF-1alpha splice variant levels were compared to clinicopathological parameters including tumour microvessel density and metastasis-free survival. RESULTS: HIF-1alpha isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1alphaTAG) and HIF-1alpha736 mRNAs were found expressed at higher levels in oestrogen receptor (OR)-negative carcinomas compared to normal/benign tissues (P = 0.009 and P = 0.004 respectively). In breast carcinoma specimens, lymph node status was significantly associated with HIF-1alphaTAG mRNA levels (P = 0.037). Significant statistical association was found between tumour grade and HIF-1alphaTAG (P = 0.048), and total HIF-1alpha (P = 0.048) mRNA levels. HIF-1alphaTAG mRNA levels were also inversely correlated with both oestrogen and progesterone receptor status (P = 0.005 and P = 0.033 respectively). Univariate analysis showed that high HIF-1alphaTAG mRNA levels correlated with shortened metastasis free survival (P = 0.01). CONCLUSIONS: Our results show for the first time that mRNA expression of a HIF-1alphaTAG splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis.See commentary: http://www.biomedcentral.com/1741-7015/8/45.

Dataset Information

Synergistic induction of galectin-1 by CCAAT/enhancer binding protein alpha and hypoxia-inducible factor 1alpha and its role in differentiation of acute myeloid leukemic cells.

Publications

Synergistic induction of galectin-1 by CCAAT/enhancer binding protein alpha and hypoxia-inducible factor 1alpha and its role in differentiation of acute myeloid leukemic cells.

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