cyclin-d1 and Leprosy

Topics: Adult; Aged; Core Binding Factor Alpha 2 Subunit; Cyclin D1; Female; Humans; Immunohistochemistry; Leprosy; Male; Middle Aged; Nerve Fibers; Receptors, Notch; Signal Transduction; Skin; Transcription Factor HES-1

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.

Topics: Blotting, Western; Bromodeoxyuridine; Cell Cycle; Cell Differentiation; Cell Nucleus; Cell Proliferation; Cell Separation; Coloring Agents; Cyclin D1; Enzyme Inhibitors; Flow Cytometry; G1 Phase; Humans; Leprosy; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); MAP Kinase Kinase 1; Microscopy, Electron; Microscopy, Fluorescence; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Biological; Mycobacterium leprae; Neuroglia; Oligonucleotide Array Sequence Analysis; Peripheral Nerves; Phosphorylation; Protein Kinase C; Protein Kinase C-epsilon; Reverse Transcriptase Polymerase Chain Reaction; S Phase; Schwann Cells; Signal Transduction; Time Factors; Transfection