Apoptotic phenotype induced by overexpression of wild-type gas3/PMP22: its relation to the demyelinating peripheral neuropathy CMT1A.

Abstract

Although the Gas3/PMP22 protein is expressed at highest levels in differentiated Schwann cells, its presence, albeit at lower levels, in non-neuronal tissues and in NIH-3T3 growth-arrested fibroblasts argues for a more general function of this protein that is uncoupled to myelin structure. We show that gas3/PMP22 overexpression in NIH-3T3 growing cells leads to an apoptotic-like phenotype, which is suppressed by antioxidants and characterized by typical membrane blebbing, rounding up, and chromatin condensation, but with no evidence of DNA fragmentation. REF-52 fibroblasts seem to be completely refractive to gas3/PMP22 overexpression. Recently, several point mutations of the human gas3/PMP22 gene have been associated with Charcot-Marie-Tooth type 1A (CMT1A), a common hereditary demyelinating neuropathy. When gas3/PMP22 point mutations (L16P, $79C, TllSM, and G150D) are similarly overexpressed in NIH-3T3 cells, the induced apoptotic-like phenotype as compared to the wild-type is significantly reduced. Both of the dominant mutations (L16P, $79C~ for CMT1A behave as dominant negatives with respect to the wild type, whereas Tl18M, the only recessive mutant described, behaves as recessive under the same coexpression experiments.These data suggest a role for altered Schwann cell apoptosis in the pathogenesis of CMT1A.

Advances in Charcot–Marie–Tooth Disease Research: Cellular Function of CMT-Related Proteins, Transgenic Animal Models, and Pathomechanisms

“…1 hese results indicate tnat PMP22 participates in fundamental mechanisms of cell growth and further demonstrate that there are cell type-specific differences in the ability to tolerate en hanced levels of PMP22. In agreement with these findings, C. Schneider provided further evidence for a link between PMP22 overexpression and programmed cell death using an expression plasmid microinjection paradigm (Fabbretti et aL, 1995). In contrast to PMP22, the overexpression, of Po protein causes no apoptosis, indicating marked differences in growth-related cellu lar functions of myelin proteins.…”

Perp is required for tissue-specific cell survival during zebrafish development

“…8 Similar to Perp, PMP22 and the EMPs can induce caspase-dependent apoptosis upon overexpression in cell culture. 9,10 However, members of the PMP22 family have also been implicated with other cellular processes, such as membrane trafficking and cell adhesion.…”

Susceptibility to p53 dependent apoptosis correlates with increased levels of Gas2 and Gas3 proteins

“…We have recently shown that Gas2 and Gas3 are involved in regulating different aspects of apoptosis. Gas2, after a specific proteolytic processing, regulates microfilament changes during apoptosis while Gas3 can trigger apoptosis when overexpressed in NIH3T3 cells (Fabbretti et al, 1995).…”

“…Removal of this domain triggers a potent cell shape and microfilament re-organizing activity in Gas2 . On the other side gas3 overexpression, by itself, is able to trigger apoptosis in NIH3T3 cells (Fabbretti et al, 1995).…”