High brain densities of the immunophilin FKBP colocalized with calcineurin.

The immunophilins cyclophilin and FK506 binding protein (FKBP) are small, predominantly soluble proteins that bind the immunosuppressant drugs cyclosporin A and FK506, respectively, with high affinity, and which seem to mediate their pharmacological actions. The Ca(2+)-dependent protein phosphatase, calcineurin, binds the cyclophilin-cyclosporin A and FKBP-FK506 complexes, indicating that calcineurin might mediate the actions of these drugs. A physiological role for the immunophilins in the nervous system is implied by a close homology between the structure of NINA A, a protein in the neural retina of Drosophila, and cyclophilin, as well as by the high density of FKBP messenger RNA in brain tissue. Here we report that the levels of FKBP and mRNA in rat brain are extraordinarily high and that their regional localization is virtually identical to that of calcineurin, indicating that there may be a physiological link between calcineurin and the immunophilins. We also show that at low concentrations FK506 and cyclosporin A enhance the phosphorylation of endogenous protein substrates in brain tissue and in intact PC12 cells, indicating that these drugs may inhibit phosphatase activity by interacting with the immunophilin-calcineurin complexes.     

Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinases.

Mitogen activated protein (MAP) kinases (MAPKs) are a family of protein-serine/threonine kinases activated as an early intracellular response to a variety of hormones and growth factors. They are unique in requiring both serine/threonine and tyrosine phosphorylation to become active and are the only examples of protein-serine/threonine kinases activated by tyrosine phosphorylation. Nerve growth factor (NGF) promotes differentiation of phaeochromocytoma (PC12) cells, which respond by conversion within hours from a chromaffin-like to a sympathetic neuron-like phenotype. NGF stimulation of PC12 cells increases the activity of two protein kinases by greater than 20-fold within minutes, both strikingly similar to MAPKs. They are inactivated by either protein-tyrosine phosphatases or the protein-serine/threonine phosphatase termed protein phosphatase 2A (ref. 8), they activate protein S6 kinase-II (refs 9, 10), and they phosphorylate identical threonine residues on myelin basic protein (our unpublished results) to those phosphorylated by other MAPKs. Immunological data indicate that these protein kinases, termed peak-I and peak-II (Fig. 1a) are probably ERK2 and ERK1, respectively, two widely expressed MAPK isoforms. Here we identify the 'MAP kinase kinases' (MAPKKs) in PC12 cells which are activated by NGF and report that MAPKKs are dependent on serine/threonine phosphorylation for activity and promote phosphorylation of serine/threonine and tyrosine residues on MAPKs.     

On the Identifiability in the Latent Budget Model

end-member model . A major drawback of the latent budget model is that, in general, the model is not identifiable, which complicates the interpretation of the model considerably. This paper studies the geometry and identifiability of the latent budget model. Knowledge of the geometric structure of the model is used to specify an appropriate criterion to identify the model. The results are illustrated by an empirical data set.     

RandomX-chromosome inactivation in interspecific hybrids ofMeriones libycus (♂) ×Meriones shawi (♀) (Rodentia: Gerbillinae)

Résumé Des cultures obtenues à partir d'hybrides femelles entre deux espèces deMeriones à 44 chromosomes et différant par l'acrocentrie (M. shawi) ou la métacentrie (M. libycus) de l'X ont permis l'étude de clones cellulaires. C'est alors tantôt l'X métacentrique, tantôt l'X acrocentrique qui se révèle inactivé («latereplicating»). Bien que la proportion 1/1, significative d'une inactivation due uniquement au hasard, n'ait pas été rigoureusement observée, ces résultats sont nettement en faveur de l'hypothèse deLyon.

---

---

Supported by Project No. 417 from the U.S. Children's Bureau and National Science Foundation (Grant No. GB 5676X).     

The role of protein phosphorylation in neural and hormonal control of cellular activity

Protein phosphorylation is now recognized to be the major general mechanism by which intracellular events in mammalian tissues are controlled by external physiological stimuli. However, only recently has the idea that different cellular functions are controlled by common protein kinases and protein phosphatases started to gain widespread acceptance. Thus there is an integrated network of regulatory pathways, mediated by phosphorylation-dephosphorylation, that allows diverse cellular events to be coordinated by neural and hormonal stimuli. The evidence that supports this concept is reviewed, with emphasis on the role of protein phosphorylation in enzyme regulation.     

Half-life of dehydroepiandrosterone sulfate (DHAS) during pregnancy]

During pregnancy the half-life of DHAS was measured after non tritiated DHAS infusion. At 30 weeks, the mean value obtained for DHAS half-life was 3.64 h +/- 0.74 and it was 3.67h +/- 0.38 at 38 weeks. The half-life of DHAS is shorter in pregnant than in non-pregnant women. Among 14 pathological pregnancies that we studied, 13 cases exhibited a DHAS half-life significantly longer than the average value obtained in normal pregnancies. In retarded fetal growth, the half-life of DHAS was more closely related to fetal than to placental weight.     

Structure of co-crystals of tropomyosin and troponin

Troponin, a Ca2+-sensitive complex, regulates the motions of tropomyosin on the thin filaments in many muscles. It has three subunits, each with a different architecture and function: TnC binds Ca2+; TnI binds to actin and inhibits contraction; and TnT binds one complex to each tropomyosin molecule. The troponin complex has an elongated shape with TnC and TnI forming a globular 'head' region and TnT a long (approximately 160 A) 'tail'. TnT binds to two widely separated regions of tropomyosin: the head region of the complex is near Cys 190 of tropomyosin and the tail region is near the overlapping joint that links the tropomyosin molecules into filaments. Here we report the X-ray structure determination at 17 A resolution of glutaraldehyde-treated tropomyosin crystals in which native troponin complex or fragments of TnT have been bound. Our results show that the amino-terminal tail end of TnT spans the head-to-tail joint of the tropomyosin filaments, and that the 'head' region of the whole troponin complex binds approximately 200 A away near residues 150-180 of the tropomyosin molecule.     

DDT-analogs as synergists for DDT

Résumé L'influence de la halogénuration du groupement méthyl dans le di-(p-chlorophényl)-méthyl-carbinol sur l'activité de ce composé comme insecticide ou synergiste du DDT a été étudiée. On essaye de donner une explication rationnelle des faits observés.