https://www.cell.com/neuron/pdf/0896-6273(90)90106-P.pdf

The regulation and function of c-fos and other immediate early genes in the nervous system.

TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue

Neuronal activity can lead to marked increases in the concentration of cytosolic calcium, which then functions as a second messenger that mediates a wide range of cellular responses. Calcium binds to calmodulin and stimulates the activity of a variety of enzymes, including calcium-calmodulin kinases and calcium-sensitive adenylate cyclases. These enzymes transduce the calcium signal and effect short-term biological responses, such as the modification of synaptic proteins and long-lasting neuronal responses that require changes in gene expression. Recent studies of calcium signal-transduction mechanisms have revealed that, depending on the route of entry into a neuron, calcium differentially affects processes that are central to the development and plasticity of the nervous system, including activity-dependent cell survival, modulation of synaptic strength, and calcium-mediated cell death.

https://science.sciencemag.org/content/sci/268/5208/239.full.pdf

Calcium signaling in neurons: molecular mechanisms and cellular consequences

We demonstrate that members of the erk-encoded family of mitogen-activated protein (MAP) kinases (pp44/42mapk/erk) and members of the rsk-encoded protein kinases (RSKs or pp90rsk) are present in the cytoplasm and nucleus of HeLa cells. Addition of growth factors to serum-deprived cells results in increased tyrosine and threonine phosphorylation and in the activation of cytosolic and nuclear MAP kinases. Activated MAP kinases then phosphorylate (serine/threonine) and activate RSKs. Concurrently, a fraction of the activated MAP kinases and RSKs enter the nucleus. In addition, a distinct growth-regulated RSK-kinase activity (an enzyme[s] that phosphorylates recombinant RSK in vitro and that may be another member of the erk-encoded family of MAP kinases) was found associated with a postnuclear membrane fraction. Regulation of nuclear MAP kinase and RSK activities by growth factors and phorbol ester is coordinate with immediate-early gene expression. Indeed, in vitro, MAP kinase and/or RSK phosphorylates histone H3 and the recombinant c-Fos and c-Jun polypeptides, transcription factors phosphorylated in a variety of cells in response to growth stimuli. These in vitro studies raise the possibility that the MAP kinase/RSK signal transduction pathway represents a protein-Tyr/Ser/Thr phosphorylation cascade with the spatial distribution and temporal regulation that can account for the rapid transmission of growth-regulating information from the membrane, through the cytoplasm, and to the nucleus.

Nuclear localization and regulation of erk- and rsk-encoded protein kinases.

I. Introduction II. Nuclear Receptors: General Concepts A. Anatomy of nuclear receptors B. Mechanisms of action III. Orphan Nuclear Receptors A. Definition B. Nomenclature C. Structural and functional diversity IV. Novel Hormone Response Systems: RXR and Its Heterodimeric Partners A. RXR: rexinoids B. PPAR: multiple ligands, multiple functions C. PXR: pregnanes, xenobiotic compounds, and benzoate derivatives D. CAR (constitutive androstane receptor): androstanes and phenobarbital E. LXR: control of cholesterol metabolism by oxysterols F. FXR: bile acids receptor V. Orphans in Search of a Home A. HNF4: diabetes and possible regulation by acyl-coenzyme A (CoA) thioesters B. FTZ-F1: steroidogenesis and sexual development C. Rev-Erb: singular members of the superfamily D. ROR: neuron development and T cell selection E. TR2: the testis receptors F. TLX: forebrain development G. COUP-TF: neurogenesis, angiogenesis, and heart development H. ERR: placenta development and control of lipid metabolism I. NGFI-B: hyp...

/pdf/orphan-nuclear-receptors-from-gene-to-function-28jgs4505b.pdf

Orphan nuclear receptors: from gene to function.

We previously identified, by cDNA cloning, a set of genes that are expressed during the G0/G1 transition (cell cycle reentry) in mouse fibroblasts. These immediate early genes are transcriptionally activated within minutes of addition of serum or purified growth factors, and their mRNAs are superinduced in the presence of protein-synthesis inhibitors. We report here that one of these genes, represented by nur/77 cDNA (originally called 3CH77), encodes a member of the superfamily of ligand-binding transcription factors that includes the steroid and thyroid hormone receptors. The nur/77 cDNA sequence encodes a protein of 601 amino acids containing two regions of sequence similarity to members of this nuclear receptor superfamily, corresponding to their DNA-binding and ligand-binding domains. These results suggest that the growth factor-inducible immediate early gene nur/77 encodes a ligand-binding protein that regulates the genomic response to growth factors.

A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily.

We have previously identified by cDNA clon- ing 5 mRNAs that appear in resting BALB/c 3T3 cells soon after growth stimulation by serum or platelet-derived growth factor. Five additional mRNAs of this class are described in this report. The mRNAs reached peak levels between 40 and 120 min after serum addition and rapidly decayed thereafter. All 10 RNAs were superinduced in the presence of cycloheximide. Nuclear run-on experiments indicated that the increase in the mRNAs is the result of rapid transcriptional activation of their genes on stimulation by serum or platelet-derived growth factor. Superinducibility by cycloheximide is due to two effects: prolonged transcription and stabilization of mRNAs. This overall pattern of regulation is similar to that of the c-fos or c-myc protooncogenes reported previously. We hypothesize that these newly identified "immediate early" genes play a role in the proliferative response induced by growth factors.

Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: Coordinate regulation with c-fos or c-myc (growth factors/gene expression/mRNA stability/protooncogenes)

Daniel Nathans

Papers

A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily.

Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: Coordinate regulation with c-fos or c-myc (growth factors/gene expression/mRNA stability/protooncogenes)