A5020566486- Endoplasmic Reticulum Stress and Disease
- Protein Kinase Regulation and GTPase Signaling
- Melanoma and MAPK Pathways
- RNA Research and Splicing
- Cancer-related Molecular Pathways
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- RNA regulation and disease
- RNA Interference and Gene Delivery
- Retinoids in leukemia and cellular processes
- Genomics and Chromatin Dynamics
- Molecular Biology Techniques and Applications
- Signaling Pathways in Disease
- Autophagy in Disease and Therapy
- RNA and protein synthesis mechanisms
- Cancer, Hypoxia, and Metabolism
- Cancer-related gene regulation
- NF-κB Signaling Pathways
- interferon and immune responses
- Monoclonal and Polyclonal Antibodies Research
- PI3K/AKT/mTOR signaling in cancer
- Cancer Cells and Metastasis
- Virus-based gene therapy research
- Epigenetics and DNA Methylation
- Nuclear Receptors and Signaling
Columbia University
2015-2025
National Institutes of Health
2005
University of Alberta
2002
Howard Hughes Medical Institute
1991-2002
University of Michigan
2002
Kyoto University
2002
San Diego State University
1998
Rockefeller University
1986-1989
Stanford University
1989
Weizmann Institute of Science
1986-1988
All eukaryotic cells respond to the accumulation of unfolded proteins in endoplasmic reticulum (ER) by signaling an adaptive pathway termed protein response (UPR). In yeast, a type-I ER transmembrane kinase, Ire1p, is proximal sensor lumen that initiates unconventional splicing reaction on HAC1 mRNA. Hac1p transcription factor required for induction UPR genes. higher cells, also induces site-2 protease (S2P)-mediated cleavage ER-localized ATF6 generate N-terminal fragment activates To...
In a variety of nerve cells the brain, action potentials activate gene expression by means Ca2+ influx. To determine how influx alters expression, we have examined pattern phosphorylation protein that binds to cAMP response element (CRE). We found purified bovine brain CRE-binding is substrate for Ca2+/calmodulin-dependent kinase II (Cam kinase) as it cAMP-dependent (kinase A). Tryptic peptide maps show same phosphorylated in vitro both A and Cam kinase. Moreover, transcription assays using...
ATF6 is a member of the basic-leucine zipper family transcription factors. It contains transmembrane domain and located in membranes endoplasmic reticulum. has been implicated reticulum (ER) stress response pathway since it can activate expression GRP78 other genes induced by ER response. appears to cleavage from membrane translocation nucleus. However, direct DNA binding had not demonstrated. In this report, we have identified consensus sequence for ATF6. This site related but distinct...
ATF6 is an endoplasmic reticulum (ER) transmembrane transcription factor that activated by the ER stress/unfolded protein response cleavage of its N-terminal half from membrane. We find stress induces to move Golgi, where it cut in luminal domain site 1 protease. contains a single with 272 amino acids oriented lumen ER. found this required for translocation Golgi and subsequent cleavage, we have mapped regions these properties. These results suggest conserved CD1 region translocation,...
We have investigated the sequence requirements for induction of human c-fos gene by epidermal growth factor (EGF), 12-O-tetradecanoyl-13-acetate (TPA), and calcium ionophore A23187 transfecting promoter mutants into HeLa A431 cells. Induction both EGF TPA in cells required presence enhancer located at -317 to -298 relative mRNA cap site. A23187, however, did not induce expression transfected gene, even though it strongly induced endogenous suggesting that has different than do TPA. also role...
Megakaryoblastic leukemia 1 (MKL1) is a myocardin-related transcription factor that we found strongly activated serum response element (SRE)-dependent reporter genes through its direct binding to (SRF). The c-fos SRE regulated by mitogen-activated protein kinase phosphorylation of ternary complex (TCF) but also RhoA-dependent pathway. mechanism this pathway unclear. Since MKL1 (also known as MAL, BSAC, and MRTF-A) broadly expressed, assessed role in induction other SRE-regulated with...
T cell receptor (TCR)–induced apoptosis of thymocytes is mediated by calcium-dependent expression the steroid receptors Nur77 and Nor1. controlled transcription factor myocyte enhancer 2 (MEF2), but how MEF2 activated calcium signaling still obscure. Cabin1, a calcineurin inhibitor, was found to regulate MEF2. normally sequestered Cabin1 in transcriptionally inactive state. TCR engagement led an increase intracellular concentration dissociation from as result competitive binding calmodulin...
Protein kinase C (PKC) is a multigene family of enzymes consisting at least 11 isoforms. It has been implicated in the induction c-fos and other immediate response genes by various mitogens. The serum element (SRE) c-fospromoter necessary sufficient for transcription serum, growth factors, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). forms complex with ternary factor (TCF) dimer (SRF). TCF target several signal transduction pathways SRF rhoA pathway. In this study we generated...
Induction of c-fos by cyclic AMP in NIH-3T3 cells is distinct from induction serum. Whereas serum mediated the response element (SRE), cAMP does not require this element. In fact, no single sequence promoter/enhancer stringently required for response. Rather, multiple elements can mediate independently. These are: (1) region -72 to -54, which contains a binding site cellular activating transcription factor (ATF); (2) -225 -99; (3) -303 -281, homologous consensus AP1; and (4) -317 -298, SRE....
Endoplasmic reticulum (ER) stress-induced activation of ATF6, an ER membrane-bound transcription factor, requires a dissociation step from its inhibitory regulator, BiP.It has been generally postulated that the BiP-ATF6 complex is result competitive binding misfolded proteins generated during stress.Here we present evidence against this model and for active regulatory mechanism complex.Contradictory to competition based on dynamic BiP our data reveal relatively stable binding.First, was...
DNA sequences encoding the human epidermal growth factor (EGF) receptor and various EGF-receptor deletion mutants were transfected into chinese hamster ovary (CHO) cells devoid of endogenous EGF receptors. A functional is expressed on surface heterologous CHO with following properties: it exhibits typical high affinity (10%; Kd = 3 X 10(-10) M) low (90%; 10(-9) binding sites for 125I-EGF; as a polypeptide 170,000 molecular weight intrinsic protein tyrosine kinase activity. stimulates...
Ca<sup>2+</sup> induction of a subset cellular and viral immediate-early activation genes in lymphocytes has been previously mapped to response elements recognized by the MEF2 family transcription factors. Here, we demonstrate that T is mediated synergy two Ca<sup>2+</sup>/calmodulin-dependent enzymes, phosphatase calcineurin, kinase type IV/Gr (CaMKIV/Gr), which promote members MEF2A MEF2D. Calcineurin up-regulates activity both factors an NFAT-dependent mechanism, while CaMKIV/Gr...
Serum response factor (SRF) gene expression in avian embryonic muscle lineages plays a central role activating α-actin activity. In early stage HH 6 embryos, SRF mRNA showed strong localization to the neural groove, primitive streak, lateral plate mesoderm, and Hensen's node, while distinct was seen later folds somites by 8. transcripts appeared precardiac splanchnic mesoderm 9 embryos detected at higher levels myocardium, somites, of 11 embryos. antibody staining demonstrated significant...
Serum response factor (SRF) is a mammalian transcription that binds to the serum element in enhancer of c-fos proto-oncogene and thus may mediate serum-induction transcription. We report here DNA binding activity recombinant SRF made Escherichia coli can be greatly enhanced by incubation protein with HeLa cell nuclear extract. The enhancing ATP or GTP dependent cofractionates kinase phosphorylates on specific tryptic peptide. Coincubation phosphatase blocks activity, further suggesting due...
Serum and growth factor regulation of c-FOS protooncogene transcription is mediated by the serum response element. A factor, binding to this element has already been identified. We demonstrate that phosphorylated in vivo on serine residues phosphatase treatment vitro abolishes its DNA-binding activity. These results show phosphorylation be required for The importance expression discussed.
The c-fos serum response element (SRE) and a sarcomeric actin promoter (CArG box) are similar in sequence recognized, respectively, by the factor (SRF) CArG-binding (CBF). Although transcriptional controls for genes rather different, SRF CBF have been found to be indistinguishable all criteria tested. They exhibited chromatographic properties, sedimentation rates, temperature stabilities. In mobility shift assays, SRE competed more strongly than CArG box formation of either SRF-SRE or...
We have purified the c-fos enhancer-binding protein from HeLa cell nuclear extracts. The key purification steps involved chromatography on a nonspecific DNA affinity column, which binding activity and other were eluted at low salt concentrations, followed by specific oligonucleotide enhancer was specifically high concentrations. had strong for dyad symmetry sequence, with an equilibrium dissociation constant of 3.3 x 10(-11) M. This least 50,000-fold stronger than that found sequences.
The IFN family of cytokines operates a frontline defense against pathogens and neoplastic cells in vivo by controlling the expression several genes. death-associated protein kinase 1 (DAPK1), an IFN-γ–induced enzyme, controls cell cycle, apoptosis, autophagy, tumor metastasis, its is frequently down-regulated number human tumors. Although biochemical action DAPK1 well understood, mechanisms that regulate are unclear. Previously, we have shown transcription factor C/EBP-β required for basal ....