Abstract:
:Nuclear expression and consequent biological action of the eukaryotic NF-kappa B transcription factor complex are tightly regulated through its cytoplasmic retention by an ankyrin-rich inhibitory protein termed I kappa B alpha. I kappa B alpha specifically binds to and masks the nuclear localization signal of the RelA subunit of NF-kappa B, thereby effectively sequestering this transcription factor complex in the cytoplasm. Specific cellular activation signals lead to the rapid proteolytic degradation of I kappa B alpha and the concomitant nuclear translocation of NF-kappa B. However, the precise biochemical mechanisms underlying the inhibitory effects of I kappa B alpha on RelA and its inducible pattern of degradation remain unclear. By using HeLa cells transfected with various cDNAs end-coding epitope-tagged mutants of I kappa B alpha, our studies demonstrate the following: (i) sequences within the 72-amino-acid N-terminal region of I kappa B alpha are required for tumor necrosis factor alpha (TNF-alpha)-induced degradation but are fully dispensable for I kappa B alpha binding to and inhibition of RelA; (ii) serine residues located at positions 32 and 36 within the N-terminal region of I kappa B alpha represent major sites of induced phosphorylation (substitution of these serine residues with alanine abrogates TNF-alpha-induced degradation of I kappa B alpha); (iii) the C-terminal 40 residues of I kappa B alpha (amino acids 277 to 317), which include a PEST-like domain, are entirely dispensable for TNF-alpha-induced degradation and inhibition of RelA; (iv) a glutamine- and leucine-rich (QL) region of I kappa B alpha located between residues 263 and 277 and overlapping with the sixth ankyrin repeat is required for both inducible degradation and inhibition of RelA function; (v) regulation of I kappa B alpha degradation by this QL-rich region appears to occur independently of phosphorylation at serines 32 and 36. These findings thus indicate that I kappa B alpha is generally organized within distinct modular domains displaying different functional and regulatory properties. These studies have also led to the identification of a novel class of dominant-negative I kappa B alpha molecules that retain full inhibitory function on NF-kappa B yet fail to undergo stimulus-induced degradation. These molecules, which lack N-terminal sequences, potently inhibit TNF-alpha-induced activation of the human immune deficiency virus type 1 kappa B enhancer, thus indicating their possible use as general inhibitors of NF-kappa B.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Sun S,Elwood J,Greene WCdoi
10.1128/mcb.16.3.1058subject
Has Abstractpub_date
1996-03-01 00:00:00pages
1058-65issue
3eissn
0270-7306issn
1098-5549journal_volume
16pub_type
杂志文章abstract::The telomeric single-strand DNA binding protein protection of telomeres 1 (POT1) protects telomeres from rapid degradation in Schizosaccharomyces pombe and has been implicated in positive and negative telomere length regulation in humans. Human POT1 appears to interact with telomeres both through direct binding to the...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.25.2.808-818.2005
更新日期:2005-01-01 00:00:00
abstract::Neuronal differentiation is tightly regulated by a variety of factors. In a search for neuron-specific genes, we identified a highly conserved novel zinc finger protein, ZNF536. We observed that ZNF536 is most abundant in the brain and, in particular, is expressed in the developing central nervous system and dorsal ro...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00362-09
更新日期:2009-07-01 00:00:00
abstract::To clarify carbon source-dependent control of the glycolytic pathway in the yeast Saccharomyces cerevisiae, we have initiated a study of transcriptional regulation of the pyruvate kinase gene (PYK). By deletion analysis of the 5'-noncoding region of the PYK gene, we have identified an upstream activating sequence (UAS...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.9.2.442
更新日期:1989-02-01 00:00:00
abstract::We have studied the abilities of different transactivation domains to stimulate the initiation and elongation (postinitiation) steps of RNA polymerase II transcription in vivo. Nuclear run-on and RNase protection analyses revealed three classes of activation domains: Sp1 and CTF stimulated initiation (type I); human i...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.16.5.2044
更新日期:1996-05-01 00:00:00
abstract::STAT3 is a ubiquitous transcription factor that is indispensable during early embryogenesis. To study the functions of STAT3 postnatally, we generated conditional STAT3-deficient mice. To that end, STAT3(lox/lox) mice were crossed with mice expressing Cre under the control of rat insulin II gene promoter (RIP-Cre mice...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.24.1.258-269.2004
更新日期:2004-01-01 00:00:00
abstract::The strength and duration of mitogen-activated protein kinase (MAPK) signaling have been shown to regulate cell fate in different cell types. In this study, a general mechanism is described that explains how subtle differences in signaling kinetics are translated into a specific biological outcome. In fibroblasts, the...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.24.1.144-153.2004
更新日期:2004-01-01 00:00:00
abstract::The doublesex and mab-3 related transcription factor 1 (Dmrt1) is a putative transcriptional regulator that is expressed exclusively in the gonads and is required for postnatal testis differentiation. Here we describe the transcriptional mechanisms regulating testis-specific expression of the Dmrt1 gene. Transient-tra...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.24.1.377-388.2004
更新日期:2004-01-01 00:00:00
abstract::Imprinted genes are expressed in a monoallelic, parent-of-origin-specific manner. Clusters of imprinted genes are regulated by imprinting control regions (ICRs) characterized by DNA methylation of one allele. This methylation is critical for imprinting; a reduction in the DNA methyltransferase DNMT1 causes a widesprea...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01278-09
更新日期:2010-08-01 00:00:00
abstract::p53 not only functions as a transcription factor but also has a direct, apoptogenic role at the mitochondria. We have discovered that DNA damage-induced p53-Bcl2 binding is associated with decreased Bcl2-Bax interaction and increased apoptotic cell death in a mechanism regulated by Bcl2's flexible loop regulatory doma...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01647-05
更新日期:2006-06-01 00:00:00
abstract::Synemin, a 230-kilodalton polypeptide component of avian muscle and erythrocyte intermediate filaments, is also found in association with the vimentin filaments of lens tissue. In chicken lens cells, synemin is bound to the core vimentin polymer with the same 180-nm periodicity that it exhibits in erythrocytes. Its so...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.4.10.1943
更新日期:1984-10-01 00:00:00
abstract::One hallmark of tumor formation is the transcriptional upregulation of human telomerase reverse transcriptase, hTERT, and the resultant induction of telomerase activity. However, little is presently understood about how hTERT is differentially activated in tumor cells versus normal somatic cells. Specifically, it is u...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.24.1.25-35.2004
更新日期:2004-01-01 00:00:00
abstract::The single-copy gene encoding the alpha subunit of glycoprotein hormones is expressed in the pituitaries of all mammals and in the placentas of only primates and horses. We have systematically analyzed the promoter-regulatory elements of the human and bovine alpha-subunit genes to elucidate the molecular mechanisms un...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.9.11.5113
更新日期:1989-11-01 00:00:00
abstract::The receptors for thyroid hormone (T3R), all-trans-retinoic acid (RAR), and 9-cis-retinoic acid (RXR) bind DNA response elements as homo- and heterodimers. The ligand-binding domains of these receptors contain nine conserved heptads proposed to play a role in dimerization. Mutant receptors with changes in the first or...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.13.9.5725
更新日期:1993-09-01 00:00:00
abstract::The onc gene (v-fes) of the acutely transforming feline sarcoma virus (Snyder-Theilen strain) has homologous cellular sequences (c-fes) in all vertebrate species, including humans. We isolated from a human DNA library recombinant phages containing overlapping c-fes sequences. The human c-fes locus spans a region of 3....
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.2.8.1014
更新日期:1982-08-01 00:00:00
abstract::The male-specific-lethal (MSL) proteins in Drosophila melanogaster serve to adjust gene expression levels in male flies containing a single X chromosome to equal those in females with a double dose of X-linked genes. Together with noncoding roX RNA, MSL proteins form the "dosage compensation complex" (DCC), which inte...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.25.14.5947-5954.2005
更新日期:2005-07-01 00:00:00
abstract::The cytoplasmic domain of the cloned erythropoietin (EPO) receptor (EPOR) contains no protein kinase motif, yet addition of EPO to EPO-responsive cells causes an increase in protein-tyrosine phosphorylation. Here we show that addition of EPO or interleukin-3 (IL-3) to an IL-3-dependent cell line expressing the wild-ty...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.12.2.706
更新日期:1992-02-01 00:00:00
abstract::Metallothioneins (MTs) are short, cysteine-rich proteins for heavy metal homeostasis and detoxification; they bind a variety of heavy metals and also act as radical scavengers. Transcription of mammalian MT genes is activated by heavy metal load via the metal-responsive transcription factor 1 (MTF-1), an essential zin...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.21.14.4505-4514.2001
更新日期:2001-07-01 00:00:00
abstract::The cytokine gamma interferon (IFN-gamma) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-gamma induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key en...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.22.8.2777-2787.2002
更新日期:2002-04-01 00:00:00
abstract::The catalytic function of Src-related tyrosine protein kinases is repressed by phosphorylation of a conserved carboxy-terminal tyrosine residue. Recent studies suggest that this inhibitory event is not the result of autophosphorylation but that it is mediated by another cytoplasmic tyrosine protein kinase, termed p50c...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.13.11.7112
更新日期:1993-11-01 00:00:00
abstract::With v-yes DNA as the probe, a human cDNA library made from placental RNA was screened under relaxed conditions, and DNA clones derived from a novel genetic locus, termed lyn, were obtained. Nucleotide sequencing revealed that lyn could encode a novel tyrosine kinase that was very similar to mouse T-lymphocyte-specifi...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.7.1.237
更新日期:1987-01-01 00:00:00
abstract::The human neuroblastoma cell line CHP100 provides a useful model system in which to study the molecular mechanisms of transcriptional regulation of the low-affinity nerve growth factor receptor (NGFR) gene during neuronal development. Basic fibroblast growth factor (bFGF) induced morphological changes in CHP100 cells,...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.12.5.2193
更新日期:1992-05-01 00:00:00
abstract::The transcriptional regulating protein of 132 kDa (TReP-132) has been identified in steroidogenic tissues, where it acts as a coactivator of steroidogenic factor 1 (SF-1). We show here that TReP-132 plays a role in the control of cell proliferation. In human HeLa cells, TReP-132 knockdown by using small interfering RN...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.25.11.4335-4348.2005
更新日期:2005-06-01 00:00:00
abstract::In eukaryotic cells, calcium entry across the cell surface activates nuclear gene expression, a process critically important for cell growth and differentiation, learning, and memory and immune cell functions. In immune cells, calcium entry occurs through store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels,...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01068-14
更新日期:2015-04-01 00:00:00
abstract::We have isolated new histone H3 mutants in Saccharomyces cerevisiae that confer phenotypes indicative of transcriptional defects. Here we describe the characterization of one such mutant, encoded by the hht2-11 allele, which contains the single amino acid change L61W in the globular domain of H3. Whole-genome expressi...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.24.2.561-572.2004
更新日期:2004-01-01 00:00:00
abstract::To examine the functional role of the interaction between Munc18c and syntaxin 4 in the regulation of GLUT4 translocation in 3T3L1 adipocytes, we assessed the effects of introducing three different peptide fragments (20 to 24 amino acids) of Munc18c from evolutionarily conserved regions of the Sec1 protein family pred...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.20.1.379-388.2000
更新日期:2000-01-01 00:00:00
abstract::During spermatogenesis, several genes are expressed in a germ cell-specific manner. Previous studies have demonstrated that rat and mouse spermatogenic cells produce a 1,700-nucleotide proenkephalin RNA, while somatic cells that express the proenkephalin gene contain a 1,450-nucleotide transcript. Using cDNA cloning, ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.10.7.3717
更新日期:1990-07-01 00:00:00
abstract::The SNAIL transcription factor contains C-terminal tandem zinc finger motifs and an N-terminal SNAG repression domain. The members of the SNAIL family have recently emerged as major contributors to the processes of development and metastasis via the regulation of epithelial-mesenchymal transition events during embryon...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01435-07
更新日期:2008-05-01 00:00:00
abstract::In Saccharomyces cerevisiae, many amino acid biosynthetic pathways are coregulated by a complex general control system: starvation for a single amino acid results in the derepression of amino acid biosynthetic genes in multiple pathways. Derepression of these genes is mediated by positive (GCN) and negative (GCD) regu...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.6.9.3150
更新日期:1986-09-01 00:00:00
abstract::A set of genes is rapidly inducible when quiescent fibroblasts are stimulated by growth factors or by the activation of temperature-sensitive retroviral protein-tyrosine kinases. Most of these so-called immediate-early genes were cloned by differential cDNA hybridization. DNA sequence analysis identified many of them ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.11.7.3682
更新日期:1991-07-01 00:00:00
abstract::Gene expression results from the coordinated actions of transcription factor proteins and coregulators. Estrogen receptor alpha (ERalpha) is a ligand-activated transcription factor that can both activate and repress the expression of genes. Activation of transcription by estrogen-bound ERalpha has been studied in deta...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00383-09
更新日期:2009-09-01 00:00:00