Comparative integromics on BMP/GDF family

Abstract. Interferon (IFN)-Ïs, including INF-Ï1, -Ï2, and -Ï3, are a newly described group of cytokines distantly related to the type I IFNs and IL-10 family members. IFN-Ï1, -Ï2, and -Ï3 bind to the same receptor (known as IL28RA) to exert their antiviral, antitumor and immunomodulatory effects. Here, we identified IL28RA genes from the genome of human, chimpanzee, macaque, orangutan, mouse, horse, rat, dog, chicken, and found that only one IL28RA existed in each genome. All the identified IL28RAs are single-pass type I membrane proteins except chicken IL28RA. They belong to the type II cytokine receptor family and contain one fibronectin type-III domain. We found human IL28RA was expressed in lymphs, testes, lymphoma, teratocarcinoma, pediatric pre-B cell acute lymphoblastic leukemia, germinal center B cells, embryonic stem cells, fetal lung, and also expressed in bladder, blood and breast cancers, glioma, head and neck cancer and lung cancer tissues. Three tumor-related transcriptional factor binding sites (AP-2, c-Jun and P53) were identified within the 1.0-kb regions upstream of the transcriptional start site of human IL28RA. Meta-analysis of the prognostic value of IL28RA genes in various cancers found that the expression of IL28RA was indeed related to the cancer prognosis in certain cancers. The STAT1 binding sites in the promoter region of IL28RA implied a specific mechanism for the amplifying effects of IFN-Ïs. The LyF-1 binding sites in the promoter region of IL28RA imply that IFN-Ïs were involved in the differentiation of early B and T cells.

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Integrative genomic analyses on IL28RA, the common receptor of interferon-λ1, -λ2 and -λ3

Yang

Luo²,

Wei³

et al. 2010

“…Expressed sequence tags (ESTs) derived from human IFN-Ïs, IL-10 and IFN-Á were searched by using the BLAST programs as previously described (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Human IFN-Ï1 (NM_172140), IFN-Ï2 (NP_742150), IFN-Ï3 (NM_172139), IL-10 (NM_000572) and IFN-Á (NM_000619) were used as query sequences for the BLAST programs.…”

Section: Identification Of Novel Ifn-mentioning

confidence: 99%

“…The identified putative IFN-Ï genes were BLASTed against the nr database of GenBank to confirm that the best hits were IFN-Ï genes. Conserved transcription factor-binding sites within promoter regions of human IFN-Ï genes, IL-10 and IFN-Á were then searched by using the Patch program (http:// www.gene-regulation.com) as well as manual inspection as previously described (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

Integrative genomic analyses on interferon-λs and their roles in cancer prediction

Yang

Wei²,

He³

2009

Abstract. Interferon (IFN)-Ïs, including IFN-Ï1, IFN-Ï2, and IFN-Ï3, are a newly described group of cytokines distantly related to the type I IFNs and IL-10 family members. Besides the antiviral activity, IFN-Ïs were reported to inhibit various tumor growths in vitro and in vivo. Herein, we identified IFN-Ï genes from the genome sequences of the human, chimpanzee, macaque, orangutan, mouse, rat and dog, and found that the locations and copy of a specific IFN-Ï varied in different genomes, not just the copy of IFN-Ïs. We found human IFN-Ïs were expressed in fetal retina, fetal brain and T cells by ESTs search. Moreover, IFN-Ïs were also found to express in bladder cancer, blood cancer, breast cancer, glioma, head and neck cancer and lung cancer tissues. Three tumorrelated transcriptional factors (steroidogenic factor-1, Wilms tumor 1 and P53) binding sites were identified within the 1.0-kb regions upstream of the transcriptional start site of human IFN-Ïs. Meta-analysis of the prognostic value of IFN-Ï genes in various cancers showed that the expression of IFN-Ïs are indeed related to the cancer prognosis in certain types of cancer. It can be predicted that IFN-Ïs take part in the cancer development by the regulation of expression of IFN-Ïs related to the SF-1, P53 and WT-1.

“…Interaction among Notch (1-3), WNT (4-6), FGF (7)(8)(9), BMP (10)(11)(12) and Hedgehog (13)(14)(15) signaling pathways constitutes the stem cell signaling network. Canonical Notch signaling in intestinal stem cells leads to Notch receptor proteolyses for the release of Notch intracellular domain (NICD), which is associated with CSL/RBPSUH and Mastermind to activate Notch target genes, such as HES1 and HES5 (16,17).…”

Section: Introductionmentioning

confidence: 99%

WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: Augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates

Katoh¹,

Katoh²

2007

Self Cite

Abstract. Notch and WNT signaling pathways are key components of the stem cell signaling network. Canonical WNT signaling to intestinal progenitor cells leads to transcriptional activation of the JAG1 gene, encoding Serratetype Notch ligand. JAG1 then binds to the Notch receptor on adjacent stem cells to induce Notch receptor proteolyses for the release of Notch intracellular domain (NICD). NICD is associated with CSL/RBPSUH and Mastermind (MAML1, MAML2, or MAML3) to activate Notch target genes, such as HES1 and HES5. Although WNT-dependent Notch signaling activation in intestinal stem cells is clarified, the effects of Notch signaling activation on WNT signaling in progenitor cells remain unclear. We searched for Notch-response element (NRE) in the promoter region of genes encoding secreted WNT signaling inhibitors, including DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1. Double NREs were identified within human DKK2 promoter by bioinformatics and human intelligence (Humint). The human DKK2 gene was characterized as Notch signaling target in intestinal stem cells. Because DKK2 is a key player in the stem cell signaling network, the DKK2 gene at human chromosome 4q25 is a candidate tumor suppressor gene inactivated due to epigenetic silencing and/or deletion. The chimpanzee DKK2 gene was identified within the NW_105990.1 genome sequence, while the cow Dkk2 gene was identified within the AC156664.2 and AC158038.2 genome sequences. Chimpanzee DKK2 and cow Dkk2 showed 98.5% and 95.8% total-aminoacid identity with human DKK2, respectively. Double NREs in human DKK2 promoter were conserved in chimpanzee DKK2 promoter, partially in rat Dkk2 promoter, but not in cow and mouse Dkk2 promoters. The Notch-DKK2 signaling loop, created or potentiated in primates, was complementary to WNT-DKK1 and BMP-IHH-SFRP1 signaling loops for negative regulation of canonical WNT signaling pathway. Together, these facts indicate that DKK2 promoter evolution resulted in the augmentation of a WNT negative regulation system in primates.