Profiling of the Bcl-2/Bcl-XL-binding sites on type 1 IP3 receptor

2012 ◽  
Vol 428 (1) ◽  
pp. 31-35 ◽  
Author(s):  
Giovanni Monaco ◽  
Marjolein Beckers ◽  
Hristina Ivanova ◽  
Ludwig Missiaen ◽  
Jan B. Parys ◽  
...  
Keyword(s):  
Binding Sites ◽  
Ip3 Receptor

Merlin cooperates with neurofibromin and Spred1 to suppress the Ras–Erk pathway

2020 ◽  
Author(s):  
Yan Cui ◽  
Lin Ma ◽  
Stephan Schacke ◽  
Jiani C Yin ◽  
Yi-Ping Hsueh ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Binding Sites ◽  
Neurofibromatosis Type ◽  
Kinase Domain ◽  
Erk Pathway ◽  
Suppressor Activity ◽  
The Third ◽  
Tumor Suppressor Activity ◽  
Multiple Signaling

Abstract The Ras–Erk pathway is frequently over-activated in human tumors. Neurofibromatosis type 1 and 2 (NF1, NF2) are characterized by multiple tumors of Schwann cell origin. The NF1 tumor suppressor neurofibromin is a principal Ras-GAP accelerating Ras inactivation, whereas the NF2 tumor suppressor merlin is a scaffold protein coordinating multiple signaling pathways. We have previously reported that merlin interacts with Ras and p120RasGAP. Here, we show that merlin can also interact with the neurofibromin/Spred1 complex via merlin-binding sites present on both proteins. Further, merlin can directly bind to the Ras-binding domain and the kinase domain of Raf1. As the third component of the neurofibromin/Spred1 complex, merlin cannot increase the Ras-GAP activity; rather, it blocks Ras binding to Raf1 by functioning as a ‘selective Ras barrier’. Merlin-deficient Schwann cells require the Ras–Erk pathway activity for proliferation. Accordingly, suppression of the Ras–Erk pathway likely contributes to merlin’s tumor suppressor activity. Taken together, our results, and studies by others, support targeting or co-targeting of this pathway as a therapy for NF2 inactivation-related tumors.

The NF-kappa B and Sp1 motifs of the human immunodeficiency virus type 1 long terminal repeat function as novel thyroid hormone response elements

1993 ◽  
Vol 13 (8) ◽  
pp. 5057-5069
Author(s):  
V Desai-Yajnik ◽  
H H Samuels
Keyword(s):  
Human Immunodeficiency Virus ◽  
Thyroid Hormone ◽  
Long Terminal Repeat ◽  
Human Immunodeficiency Virus Type ◽  
Binding Sites ◽  
Nf Kappa B ◽  
Response Elements ◽  
Immunodeficiency Virus ◽  
Hiv 1

We report that thyroid hormone (T3) receptor (T3R) can activate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). Purified chick T3R-alpha 1 (cT3R-alpha 1) binds as monomers and homodimers to a region in the LTR (nucleotides -104 to -75 [-104/-75]) which contains two tandem NF-kappa B binding sites and to a region (-80/-45) which contains three Sp1 binding sites. In contrast, human retinoic acid receptor alpha (RAR-alpha) and mouse retinoid X receptor beta (RXR-beta) do not bind to these elements. However, RXR-beta binds to these elements as heterodimers with cT3R-alpha 1 and to a lesser extent with RAR-alpha. Gel mobility shift assays also revealed that purified NF-kappa B p50/65 or p50/50 can bind to one but not both NF-kappa B sites simultaneously. Although the binding sites for p50/65, p50/50, and T3R, or Sp1 and T3R, overlap, their binding is mutually exclusive, and with the inclusion of RXR-beta, the major complex is the RXR-beta-cT3R-alpha 1 heterodimer. The NF-kappa B region of the LTR and the NF-kappa B elements from the kappa light chain enhancer both function as T3 response elements (TREs) when linked to a heterologous promoter. The TREs in the HIV-1 NF-kappa B sites appear to be organized as a direct repeat with an 8- or 10-bp gap between the half-sites. Mutations within the NF-kappa B motifs which eliminate binding of cT3R-alpha 1 also abolish stimulation by T3, indicating that cT3R-alpha 1 binding to the Sp1 region does not independently mediate activation by T3. The Sp1 region, however, is converted to a functionally strong TRE by the viral tat factor. These studies indicate that the HIV-1 LTR contains both tat-dependent and tat-independent TREs and reveal the potential for T3R to modulate other genes containing NF-kappa B- and Sp1-like elements. Furthermore, they indicate the importance of other transcription factors in determining whether certain T3R DNA binding sequences can function as an active TRE.

scholarly journals A proliferative p53-responsive element mediates tumor necrosis factor alpha induction of the human immunodeficiency virus type 1 long terminal repeat.

1995 ◽  
Vol 15 (6) ◽  
pp. 3450-3459 ◽  
Author(s):  
A Gualberto ◽  
M L Hixon ◽  
T S Finco ◽  
N D Perkins ◽  
G J Nabel ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Tumor Necrosis Factor ◽  
Long Terminal Repeat ◽  
Binding Sites ◽  
Tumor Necrosis ◽  
Terminal Repeat ◽  
Mutant P53 ◽  
Immunodeficiency Virus ◽  
Necrosis Factor

Transforming mutants of the p53 tumor suppressor gene can positively regulate transcription from several promoters that do not contain known p53 binding sites. Here, we report the identification of a novel p53 binding site in the human immunodeficiency virus long terminal repeat that specifically mediates mutant p53 transactivation. This DNA element was bound by endogenous Jurkat p53 when these cells were stimulated by tumor necrosis factor. Mutation of this sequence inhibited p53 transactivation and tumor necrosis factor inducibility of the human immunodeficiency virus type 1 long terminal repeat. In addition, this DNA element was found to be sufficient to confer mutant p53 responsiveness on a heterologous minimal promoter. It has been hypothesized that transforming mutants of p53 represent a proliferative conformational stage that can be adopted by the native protein under stimulation by growth factors. The data presented suggest that proliferative and antiproliferative p53 conformations recognize different DNA binding sites in order to mediate distinct biological functions. Thus, transforming mutants of p53 that fold into the proliferative conformation would favor proliferative over antiproliferative functions.

Analysis of the human CD10/neutral endopeptidase 24.11 promoter region: two separate regulatory elements

Blood ◽  
1995 ◽  
Vol 85 (11) ◽  
pp. 3199-3207 ◽  
Author(s):  
F Ishimaru ◽  
MA Shipp
Keyword(s):  
Binding Sites ◽  
Lymphoblastic Leukemia ◽  
Regulatory Region ◽  
Neutral Endopeptidase ◽  
Regulatory Elements ◽  
Control Element ◽  
Regulatory Regions ◽  
Endopeptidase 24.11

The cell surface zinc metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) is expressed on normal and malignant lymphoid progenitors, granulocytes, and a variety of epithelial cells. To further define the tissue-specific and developmentally related expression of CD10/NEP, we have characterized two separate regulatory regions that control the transcription of 5′ alternatively spliced CD10/NEP transcripts. These type 1 and 2 CD10/NEP regulatory regions are both characterized by the presence of multiple transcription initiation sites and the absence of classic TATA boxes and consensus initiator elements. The purine-rich type 1 regulatory region, which includes 5′ UTR exon 1 sequence, is characterized by multiple putative PU.1 binding sites and consensus ets-binding motifs. In marked contrast, the GC-rich type 2 regulatory region contains multiple putative Sp1 binding sites, a potential consensus retinoblastoma control element (RCE), and an inverted CCAAT box. In the majority of tissues examined to date, type 2 CD10/NEP transcripts were more abundant; the abundance of type 1 transcripts was more variable, with the highest type 1 levels in fetal thymus and certain lymphoblastic leukemia cell lines.

scholarly journals Zinc partitions IGFs from soluble IGF binding proteins (IGFBP)-5, but not soluble IGFBP-4, to myoblast IGF type 1 receptors

2004 ◽  
Vol 180 (2) ◽  
pp. 227-246 ◽  
Author(s):  
RH McCusker ◽  
J Novakofski
Keyword(s):  
Cell Surface ◽  
Binding Sites ◽  
Affinity Binding ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Igf Binding ◽  
Igf Receptor ◽  
Igf Binding Protein

Zinc (Zn(2+)), a multifunctional micronutrient, was recently shown to lower the affinity of cell-associated insulin-like growth factor (IGF) binding protein (IGFBP)-3 and IGFBP-5 for both IGF-I and IGF-II, but to increase the affinity of the cell surface type 1 IGF receptor (IGF-1R) for the same two ligands. However, there is a need for data concerning the effects of Zn(2+) on soluble IGFBPs and the type 2 IGF receptor (IGF-2R). In the current work, we demonstrate that Zn(2+) affects the affinity of IGFBP-5 secreted by myoblasts but not IGFBP-4. Zn(2+), at physiological levels, depressed binding of both IGF-I and IGF-II to IGFBP-5, affecting (125)I-IGF-I more than (125)I-IGF-II. Both (125)I-IGF-I and (125)I-IGF-II bound to high and low affinity sites on IGFBP-5. Zn(2+) converted the high affinity binding sites of IGFBP-5 into low affinity binding sites. An IGF-I analog, (125)I-R(3)-IGF-I, did not bind to the soluble murine IGFBP-5. Zn(2+) also decreased the affinity of the IGF-2R on L6 myoblasts. In contrast, Zn(2+) increased IGF-I, IGF-II and R(3)-IGF-I binding to the IGF-1R by increasing ligand binding affinity on both P(2)A(2a)-LISN and L6 myoblasts. Soluble IGFBP-5 and IGFBP-4 depressed the binding of (125)I-IGF-I and (125)I-IGF-II to the IGF-1R, but did not affect binding of (125)I-R(3)-IGF-I. By depressing the association of the IGFs with soluble IGFBP-5, Zn(2+) partitioned (125)I-IGF-I and (125)I-IGF-II from soluble IGFBP-5 onto cell surface IGF-1Rs. This effect is not seen when soluble L6-derived IGFBP-4 is present in extracellular fluids. We introduce a novel mechanism by which the trace micronutrient Zn(2+) may alter IGF distribution, i.e. Zn(2+) acts to increase IGF-1R binding at the expense of IGF binding to soluble IGFBP-5 and the IGF-2R.

scholarly journals Repression of Human T-lymphotropic virus type 1 Long Terminal Repeat sense transcription by Sp1 recruitment to novel Sp1 binding sites

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Sylvain Fauquenoy ◽  
Gwenaëlle Robette ◽  
Anna Kula ◽  
Caroline Vanhulle ◽  
Sophie Bouchat ◽  
...  
Keyword(s):  
Long Terminal Repeat ◽  
Virus Type ◽  
Binding Sites ◽  
Terminal Repeat ◽  
T Lymphotropic Virus

scholarly journals Functional Interactions between C/EBP, Sp1, and COUP-TF Regulate Human Immunodeficiency Virus Type 1 Gene Transcription in Human Brain Cells

2000 ◽  
Vol 74 (1) ◽  
pp. 65-73 ◽  
Author(s):  
Christian Schwartz ◽  
Philippe Catez ◽  
Olivier Rohr ◽  
Dominique Lecestre ◽  
Dominique Aunis ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Transcription Factor ◽  
Human Brain ◽  
Gene Transcription ◽  
Binding Sites ◽  
Brain Cells ◽  
Functional Interactions ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infects the central nervous system (CNS) and plays a direct role in the pathogenesis of AIDS dementia. However, mechanisms underlying HIV-1 gene expression in the CNS are poorly understood. The importance of CCAAT/enhancer binding proteins (C/EBP) for HIV-1 expression in cells of the immune system has been recently reported. In this study, we have examined the role and the molecular mechanisms by which proteins of the C/EBP family regulate HIV-1 gene transcription in human brain cells. We found that NF-IL6 acts as a potent activator of the long terminal repeat (LTR)-driven transcription in microglial and oligodendroglioma cells. In contrast, C/EBPγ inhibits NF-IL6-induced activation. Consistent with previous data, our transient expression results show cell-type-specific NF-IL6-mediated transactivation. In glial cells, full activation needs the presence of the C/EBP binding sites; however, NF-IL6 is still able to function via the minimal −40/+80 region. In microglial cells, C/EBP sites are not essential, since NF-IL6 acts through the −68/+80 LTR region, containing two binding sites for the transcription factor Sp1. Moreover, we show that functional interactions between NF-IL6 and Sp1 lead to synergistic transcriptional activation of the LTR in oligodendroglioma and to mutual repression in microglial cells. We further demonstrate that NF-IL6 physically interacts with the nuclear receptor chicken ovalbumin upstream promoter transcription factor (COUP-TF), via its DNA binding domain, in vitro and in cells, which results in mutual transcriptional repression. These findings reveal how the interplay of NF-IL6 and C/EBPγ, together with Sp1 and COUP-TF, regulates HIV-1 gene transcription in brain cells.

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