Concentration-dependent regulation of neuronal gene expression by nerve growth factor

NGF is a neurotrophic protein that promotes the survival, growth, and differentiation of developing sympathetic neurons. To directly determine the effects of different concentrations of NGF on neuronal gene expression, we examined mRNAs encoding the p75 low-affinity NGF (LNGF) receptor, T alpha 1 alpha-tubulin (T alpha 1), and tyrosine hydroxylase (TH) in pure cultures of rat sympathetic neurons from postnatal day 1 superior cervical ganglia. Studies of the timecourse of gene expression during 2 wk in culture indicated that a 5-d incubation period would be optimal for the concentration-effect studies. Analysis of RNA isolated from neurons cultured in 2-200 ng/ml 2.5S NGF for 5 d revealed that, as the NGF concentration increased, neurons expressed correspondingly increased levels of all three mRNAs. Both LNGF receptor and TH mRNAs increased seven-fold, and T alpha 1 mRNA increased four-fold in neurons cultured in 200 versus 10 ng/ml NGF. In contrast, T26 alpha-tubulin mRNA, which is constitutively expressed, did not alter as a function of NGF concentration. When neurons were initially cultured in 10 ng/ml NGF for 5 d, and then 200 ng/ml NGF was added, LNGF receptor, T alpha 1, and TH mRNAs all increased within 48 h. The timecourse of induction differed: T alpha 1 mRNA was maximal by 5 h, whereas LNGF receptor and TH mRNAs first began to increase at 12 h after the NGF increase. These experiments show that NGF regulates expression of a subset of mRNAs important to neuronal growth and differentiation over a broad concentration range, suggesting that the effects of NGF may be mediated by more than just a single receptor operating at one fixed affinity. These results also suggest a mechanism for coupling neuronal synthesis of axonal proteins to increases in size of the innervated target territory during growth of the organism.     

Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage

Familial dysautonomia(FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1(ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different c...     

Virus-encoded microRNAs: novel regulators of gene expression

MicroRNAs (miRNAs) are a class of small RNAs that have recently been recognized as major regulators of gene expression. They influence diverse cellular processes ranging from cellular differentiation, proliferation, apoptosis and metabolism to cancer. Bioinformatic approaches and direct cloning methods have identified >3500 miRNAs, including orthologues from various species. Experiments to identify the targets and potential functions of miRNAs in various species are continuing but the recent discovery of virus-encoded miRNAs indicates that viruses also use this fundamental mode of gene regulation. Virus-encoded miRNAs seem to evolve rapidly and regulate both the viral life cycle and the interaction between viruses and their hosts.     

Role of protein kinase C in the regulation of glucagon gene expression by arginine

The cellular mechanism of glucagon gene expression in intact rat islets and their synthesis and release of glucagon were investigated. Arginine significantly increased the amounts of preproglucagon mRNA and glucagon in the islets and glucagon release. H-7, a specific inhibitor of protein kinase C (PKC), significantly inhibited these effects of arginine. However, H-8, a potent inhibitor of cyclic nucleotide-dependent protein kinases, did not affect the arginine-induced biosynthesis of glucagon or glucagon release. These results suggest that the regulation of glucagon gene expression by arginine is mediated by PKC, not by cyclic nucleotide-dependent protein kinases.     

p63 regulation by microRNAs

Wafik S. El-Deiry, M.D., Ph.D., American Cancer Society Research Professor at the University of Pennsylvania, organized and hosted in Philadelphia the 199th Meeting of the Interurban Clinical Club (interurbanclinicalclub.org) started by Sir William Osler in 1905. The Scientific Meeting was held at the College of Physicians of Philadelphia and featured outstanding presentations of the most exciting biomedical research in Philadelphia. The evening black-tie dinner event was held at the historic Union League of Philadelphia where Margaret Foti, Ph.D., M.D. (h.c.), Chief Executive Officer of the American Association for Cancer Research addressed the attendees.