Regulatory elements and transcription factors controlling basal and cytokine-induced expression of the gene encoding intercellular adhesion molecule 1.

Hou, Jinzhao; Baichwal, Vijay; Cao, Zhaodan

doi:10.1073/pnas.91.24.11641

Cited by 201 publications

(137 citation statements)

References 34 publications

Supporting

Mentioning

131

Contrasting

Order By: Relevance

“…3E, bag3 silencing results in reduced amounts of phosphorylated GST-IκBα. Consistently, the mRNA levels of ICAM-1, a gene highly regulated by NF-κB (38), are reduced in cells transfected with bag3 siRNA (Fig. 3F), confirming the effect of BAG3 on NF-κB activity.…”

Section: Resultssupporting

confidence: 67%

IKKγ protein is a target of BAG3 regulatory activity in human tumor growth

Ammirante

Rosati

Arra³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

101

123

View full text Add to dashboard Cite

BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-κB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKγ, increasing availability of IKKγ and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-κB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.BAG3 | IKK-gamma | apoptosis

show abstract

Section: Resultssupporting

confidence: 67%

IKKγ protein is a target of BAG3 regulatory activity in human tumor growth

Ammirante

Rosati

Arra³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

101

123

View full text Add to dashboard Cite

show abstract

“…C, ICAM-1 sequence (Ϫ130 to Ϫ81) without or with inverted repeat or GC box mutations were used to define binding sites for Stat1 and Sp1. D, nuclear protein extracts from unstimulated hTBEC monolayers were treated with no antiserum Stat1/Sp1 Transcriptional Synergy 30265 kine-independent) basal promoter activity (10,23,25,27). Basal activity and IFN-␥ responsiveness are restored when the Stat1-binding site is placed in front of a heterologous promoter (10), but these systems may include other DNA elements that could synergize with the Stat1 site (as noted below).…”

Section: Fig 2 Sp1 Binds 3-adjacent To Stat1 In the Icam-1 Gene Irementioning

confidence: 99%

Stat1 Depends on Transcriptional Synergy with Sp1

Look

Pelletier

Tidwell

et al. 1995

Journal of Biological Chemistry

252

158

View full text Add to dashboard Cite

STAT (signal transducer and activator of transcription) proteins combine with cytokine receptors and receptor-associated kinases in distinct protein/protein interactions that are critical for STAT-dependent signal transduction events, but the nature of any subsequent STAT interactions with DNA-binding proteins in the nucleus is less certain. Based on assays of DNA/protein binding and activity of transfected reporter plasmids, we determined that occupation of contiguous DNA-binding sites for Stat1 (the first member of the STAT family) and the transcriptional activator Sp1 are both required for full activation of the intercellular adhesion molecule-1 gene by interferon-␥. Thus, Stat1 binding to DNA cannot by itself be equated with biologic actions of Stat1. In co-immunoprecipitation experiments, we also obtained evidence of direct and selective Stat1/Sp1 interaction (in primary culture cells without overexpression), further indicating that Stat1/Sp1 synergy confers an element of specificity in the pathway leading to cytokine-activated transcription and cytokine-dependent immunity and inflammation. STAT1 proteins act as critical intermediates in cytokine-dependent gene activation based on their dual capacities for signal transduction (at the cell surface) and activation of transcription (in the nucleus) (1). Signal transduction depends on programmed assembly of cytokine receptors, receptor-associated JAK kinases, and in some cases serine kinases, that recruit and activate specific STAT proteins (2-4). Phosphorylated/activated STATs then dimerize, translocate to the nucleus, and direct transcription of specific target genes. For example, the first member of the STAT family (designated Stat1␣) undergoes tyrosine 701 and serine 727 phosphorylation in response to IFN-␥ (5). This activation step is triggered by IFN-␥-dependent oligomerization of the IFN-␥ receptor and consequent cross-phosphorylation of receptor-associated Jak1 and Jak2 kinases and the receptor ␣-chain (6). Receptor phosphorylation enables ␣-chain recruitment of Stat1 via its SH2 domain. Stat1 then undergoes phosphorylation and release from the receptor as a homodimer that can translocate to the nucleus and bind to a specific DNA element (7,8). Thus, distinct protein/protein interactions are critical for Stat1-dependent signal transduction events at the IFN-␥ receptor, but the nature of Stat1 interactions with other proteins (especially other transcription factors) in the nucleus is less certain. In the present report, we take advantage of a primary cell culture model with selective IFN-␥ responsiveness of the intercellular adhesion molecule-1 (ICAM-1) gene (9, 10) in order to study the basis for Stat1-dependent transcription. The results offer the first evidence that Stat1-mediated transactivation depends on synergistic interaction with another transcriptional activator (Sp1). EXPERIMENTAL PROCEDURESMaterials-Recombinant human IFN-␥ was from Genentech (San Francisco, CA); unlabeled dATP and dGTP were from Boehringer Mannheim; [␣-32 P]dCTP was from DuPo...

show abstract

“…NF-B⅐C/EBP-␣ heterodimers are formed through the interaction of the Rel homology region of NF-B proteins with leucine zipper domains within b-ZIP regions of C/EBP transcription factors. Heterodimerization is facilitated by the presence of adjacent B and C/EBP binding sites in several genes encoding cytokines (IL-6, IL-8, G-CSF, neutrophil-activating peptide ENA-78, MGSA/GRO) (16, 19 -24), acute phase proteins (angiotensinogen, serum amyloid A protein, ␣ 1 -acid glycoprotein, TSG-14/ PTX-3) (25)(26)(27)(28) or adhesion receptors (intercellular adhesion molecule-1) (29). The presence of C/EBP⅐NF-B protein heterocomplexes has been demonstrated in intact cells (17,30).…”

mentioning

confidence: 99%