02920nas a2200553   4500000000100000008004100001260001600042653002200058653002200080653001500102653002500117653001700142653002300159653002000182653002000202653001400222653002200236653001900258653001300277653001100290653001200301653005700313653002400370653002500394653002900419653003900448653003900487653002300526653002500549653001400574653004400588653002200632653002000654653002100674653002900695653005200724653001200776653001800788653002400806653001700830653001700847100001400864700001700878245014800895300001201043490000801055520128901063022001402352       2005                            d  c2005 Jun 2810aBlotting, Western10aBromodeoxyuridine10aCell Cycle10aCell Differentiation10aCell Nucleus10aCell Proliferation10aCell Separation10aColoring Agents10aCyclin D110aEnzyme Inhibitors10aFlow Cytometry10aG1 Phase10aHumans10aleprosy10aLymphocyte Specific Protein Tyrosine Kinase p56(lck)10aMAP Kinase Kinase 110aMicroscopy, Electron10aMicroscopy, Fluorescence10aMitogen-Activated Protein Kinase 110aMitogen-Activated Protein Kinase 310aModels, Biological10aMycobacterium leprae10aNeuroglia10aOligonucleotide Array Sequence Analysis10aPeripheral nerves10aPhosphorylation10aProtein Kinase C10aProtein Kinase C-epsilon10aReverse Transcriptase Polymerase Chain Reaction10aS Phase10aSchwann Cells10aSignal Transduction10aTime Factors10aTransfection1 aTapinos N1 aRambukkana A00aInsights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli.  a9188-930 v1023 a<p>Activation of extracellular signal-regulated kinase (Erk) 1/2, which plays a critical role in diverse cellular processes, including cell proliferation, is known to be mediated by the canonical Raf-mitogen-activated protein kinase kinase (MEK) kinase cascade. Alternative MEK-independent signaling pathways for Erk1/2 activation in mammalian cells are not known. During our studies of human primary Schwann cell response to long-term infection of Mycobacterium leprae, the causative organism of leprosy, we identified that intracellular M. leprae activated Erk1/2 directly by lymphoid cell kinase (p56Lck), a Src family member, by means of a PKCepsilon-dependent and MEK-independent signaling pathway. Activation of this signaling induced nuclear accumulation of cyclin D1, G1/S-phase progression, and continuous proliferation, but without transformation. Thus, our data reveal a previously unknown signaling mechanism of glial cell proliferation, which might play a role in dedifferentiation as well as nerve regeneration and degeneration. Our findings may also provide a potential mechanism by which an obligate intracellular bacterial pathogen like M. leprae subverts nervous system signaling to propagate its cellular niche for colonization and long-term bacterial survival.</p>  a0027-8424