Expression of the 90K Immunostimulator Gene Is Controlled by a Promoter with Unique Features

Brakebusch, Cord; Jallal, Bahija; Fusco, O.; Iacobelli, Stéfano; Ullrich, Axel

doi:10.1074/jbc.272.6.3674

Cited by 12 publications

(22 citation statements)

References 42 publications

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“…Additionally, the mouse CyCAP gene reported here has an intron-exon structure and promoter sequence identical to the mouse 90K gene, which was isolated by virtue of hybridization to hMac-2-BP cDNA (ref. 38 and data not shown). These data establish CyCAP as the sequence most similar to hMac-2-BP in the mouse genome.…”

Section: Discussionmentioning

confidence: 99%

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Cyclophilin C-associated protein: A normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responsesin vivo

Trahey

1999

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

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Mouse cyclophilin C-associated protein (Cy-CAP) is a member of the scavenger-receptor cysteine-rich domain superfamily and is 69% identical to the human Mac-2 binding protein. Here, we show that CyCAP is a widely expressed secreted glycoprotein that modulates the host response to endotoxin. Gene-targeted CyCAP-deficient mice are more sensitive to the lethal effects of endotoxin. In response to endotoxin, CyCAPdeficient mice overproduced interleukin 12 and interferon-␥ systemically and tumor necrosis factor ␣ locally; these are proinflammatory molecules that also promote T helper 1 responses. Furthermore, macrophages stimulated in vitro with endotoxin in serum deficient in CyCAP secreted more tumor necrosis factor ␣, supporting the proposal that CyCAP specifically down-modulates endotoxin signaling.

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Section: Discussionmentioning

confidence: 99%

“…Several groups have proposed that hMac-2-BP may be involved in host defense to pathogens (8,12,16,38). Biochemical studies showing an interaction between hMac-2-BP and LPS and its receptor CD14 (17) suggested that the role of hMac-2-BP in defense may be through the host response to endotoxin.…”

Section: Discussionmentioning

confidence: 99%

Cyclophilin C-associated protein: A normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responsesin vivo

Trahey

1999

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

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“…A few promoters have been described that, like the DD3 promoter, are TATA-less and initiator-less and are not GC-rich (Ref. 29, and references therein). No further similarities to these gene promoters could be identified.…”

Section: Discussionmentioning

confidence: 99%

Isolation and Characterization of the Promoter of the Human Prostate Cancer-specific DD3 Gene

Verhaegh¹,

Bokhoven²,

Smit³

et al. 2000

Journal of Biological Chemistry

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Recently, we have described a novel gene, DD3, which is one of the most prostate cancer-specific genes described to date (Bussemakers, M. J. G., van Bokhoven, A., Verhaegh, G. W., Smit, F. P., Karthaus, H. F. M., Schalken, J. A., Debruyne, F. M. J., Ru, N., and Isaacs, W. B. (1999) Cancer Res. 59, 5975-5979). The prostate cancer-specific expression of DD3 indicates that the DD3 gene promoter is a promising tool for the treatment of prostate cancer. To identify the promoter elements that are responsible for the prostate cancer-specific expression of DD3, we have isolated and characterized the DD3 promoter. Sequence analysis of the DD3 5-flanking region was performed and several promoter-human growth hormone reporter constructs were prepared, which were transiently transfected in the DD3-positive cell line LNCaP and several DD3-negative cell lines. Using a 500-base pair DD3 promoter construct, we could detect promoter activity in LNCaP cells, which was not affected by increasing the size of the constructs. Truncated constructs, however, showed an increased transcriptional activity, suggesting the presence of a silencer that negatively regulates the expression of DD3. DNase-I footprint analysis, using nuclear extracts from LNCaP cells, revealed the presence of three DNase-Iprotected areas within the DD3 proximal promoter. We show that the high mobility group I(Y) protein binds to one of the DNase-I-protected areas and recruits another, yet unidentified, protein to the DD3 promoter in LNCaP cells.Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population (1). When this carcinoma has locally or distantly spread, no curative therapy can be offered. Because there is no effective treatment available for patients with advanced and/or hormone-refractory prostate cancer, there is an urgent need to develop new approaches to treat patients with progressive prostate cancer. A better understanding of the molecular changes associated with the onset and progression of prostate cancer may provide a rational basis for the development of new treatment modalities. For example, gene therapy using prostate-specific gene promoters, i.e. linking up prostatespecific promoter sequences to genes that suppress tumor cell growth, induce apoptosis, and/or kill tumor cells, may provide a new way to attack this mordacious disease (2, 3).A number of human genes have been identified that are specifically expressed in the human prostate, including prostate-specific antigen (PSA) 1 (e.g. Ref. (9), and prostate stem cell antigen (10). The promoter sequences responsible for the prostate-specific expression of these genes have been cloned, and the unraveling of their transcriptional regulation is ongoing and will provide prostate-specific promoter fragments that can activate therapeutic agents selectively in prostatic (cancer) cells.The PSA gene promoter has been most extensively studied and revealed the existence of a proximal prostate-specific promoter with an upstr...

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“…2). This region has been reported to be the minimal promoter of the mouse and human 90K genes (35,36) and, as will be evident below, corresponds to the minimal functional promoter of the rat 90K as well.…”

Section: Characterization Of the 5ј-flanking Region Of The Rat 90k Genementioning

confidence: 99%

“…Sequence alignments and comparisons with the human and mouse 5Ј-flanking regions (35,36) were performed using Gene Works (IntelliGenetics, Inc., Mountain View, CA).…”

Section: Dna Sequencing and Sequence Analysismentioning

confidence: 99%

Upstream Stimulatory Factor Regulates Constitutive Expression and Hormonal Suppression of the 90K (Mac-2BP) Protein

et al. 2007

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We previously reported that hormones important for the normal growth and function of FRTL-5 rat thyroid cells, TSH, or its cAMP signal plus insulin or IGF-I, could transcriptionally suppress constitutive and ␥-interferon (IFN)-increased synthesis of the 90K protein (also known as Mac-2BP). Here we cloned the 5-flanking region of the rat 90K gene and identified a minimal promoter containing an interferon response element and a consensus E-box or upstream stimulator factor (USF) binding site, which are highly conserved in both the human and murine genes. We show that suppression of constitutive and ␥-IFN- The function of 90K is not known, although several lines of evidence support a role for the protein in the host immune defense. First, 90K is a member of a family of transmembrane or secreted glycoproteins containing a scavenger receptor, cysteine-rich domain (9, 10). Proteins containing a scavenger receptor, cysteine-rich domain are expressed by immunocompetent cells (B and T lymphocytes, macrophages) and are implicated in immune defense (9, 11-13). Second, in vitro generation of cytotoxic effector cells (natural killer and lymphokine-activated killer) has been observed after exposure of peripheral blood mononuclear cells (PBMCs) to 90K (9). Third, 90K increases cytokine production by PBMCs (9, 12) and accessory cells (12,14). Finally, 90K increases major histocompatibility (MHC) class I antigen expression in human breast cancer cells (15).A rat 90K was recently cloned (16) and found to be homologous to human 90K (9, 10) and to mouse adherent macrophage protein (also known as CyCap, Cyclophilin C associated protein) (17,18). In rat thyroid FRTL-5 cells, 90K is increased by ␥-interferon (IFN), as in humans and mice, and acts in an autocrine or paracrine/exocrine manner to increase MHC class I (16). Hormones that regulate the growth and function of FRTL-5 cells, particularly TSH/cAMP plus insulin/IGF-I (19 -23), coordinately decrease MHC class I and 90K expression (16).The ability of TSH/cAMP plus insulin/IGF-I to decrease MHC class I (24) has been explained by a complex, interlocking array of trans factors and cis elements (25-30). In contrast, the mechanisms involved in hormonal suppression of 90K are unknown.Here we report the cloning of the 5Ј flanking region of the rat 90K gene and the identification of the critical regulatory element responsible for the suppression of 90K expression by TSH/cAMP plus insulin/IGF-I. We show that this element controls basal expression of 90K, is conserved in the human and mouse promoter, and corresponds to an E-box that is sensitive to regulation by the basic helix-loop-helix leucine zipper proteins, upstream stimulator factor (USF)-1 and -2.

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Expression of the 90K Immunostimulator Gene Is Controlled by a Promoter with Unique Features

Cited by 12 publications

References 42 publications

Cyclophilin C-associated protein: A normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responsesin vivo

Cyclophilin C-associated protein: A normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responsesin vivo

Isolation and Characterization of the Promoter of the Human Prostate Cancer-specific DD3 Gene

Upstream Stimulatory Factor Regulates Constitutive Expression and Hormonal Suppression of the 90K (Mac-2BP) Protein

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