The Cloning and Characterization of the Human Neurofibromatosis Type 2 Gene

Note:Neurofibromatosis type 2, (NF2), or central neurofibromatosis, occurs with a frequency of 1:37 500 in the general population and is characterized by the development of vestibular schwannomas, meningiomas, spinal schwannomas, ependymomas and juvenile posterior lenticular opacities. Cytogenetic and mutation studies showed that there was a frequent loss of chromosome 22 in sporadic schwannomas and meningiomas implicating the presence of a tumour suppressor gene on this chromosome patterned along the lines of the Knudson model of tumour suppressors. The gene was mapped to chromosome 22q using RFLP markers and the region was further narrowed by the generation of a genetic map of chromosome 22 and new highly informative markers. Using the positional cloning efforts described in this thesis, the NF2 gene was identified. […]Les neurofibromatoses sont les maladies génétiques du système nerveux les plus fréquentes. La neurofibromatose de type 1 (NF1) ou maladie de von Recklinhausen ou neurofibromatose périphérique a une incidence de 1:3500 dans la population générale et est caractérise par le développement de neurofibromes, de gliomes optiques, de taches café-au-lait, de nodules de Lisch, malformations des os et muscles squelettiques ainsi que des problèmes d'apprentissage. Le gène responsable de la neurofibromatose de type I a été localise sur le chromosome 17 et isolé grâce aux techniques de clonage positionnel conventionnelles. VARN messager correspondant, d'une taille de 11-13 kb, est exprimé de façon ubiquitaire. […

The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1

Akt kinases mediate cell growth and survival. Here, we report that a pro-apoptotic kinase, Mst1/STK4, is a physiological Akt1 interaction partner. Mst1 was identified as a component of an Akt1 multiprotein complex isolated from lipid raft-enriched fractions of LNCaP human prostate cancer cells. Endogenous Mst1, along with its paralog, Mst2, acted as inhibitors of endogenous Akt1. Surprisingly, mature Mst1 as well as both of its caspase cleavage products, which localize to distinct subcellular compartments and are not structurally homologous, complexed with and inhibited Akt1. cRNAs encoding full-length Mst1, and N- and C-terminal caspase Mst1 cleavage products, reverted an early lethal phenotype in zebrafish development induced by expression of membrane-targeted Akt1. Mst1 and Akt1 localized to identical subcellular sites in human prostate tumors. Mst1 levels declined with progression from clinically localized to hormone refractory disease, coinciding with an increase in Akt activation with transition from hormone naïve to hormone-resistant metastases. These results position Mst1/2 within a novel branch of the phosphoinositide 3-kinase/Akt pathway and suggest an important role in cancer progression