PARENT SESSION
3:45 PM to 5:15 AM
Sunday, April 21, 2002
Mini-Symposium 5
Oxygenation and Stress Response
Room: Nevada 1-2
, Co-Chair: Koch, Cameron1; Mason, Kathy21University of Pennsylvania, Philadelphia, PA2MD Anderson Cancer Center, Houston, TX
(MS05-4) Isoform specificity of redox-mediated TGF-
activation.
Jobling, Michael*,1, Finnigan, Monica1, Barcellos-Hoff, Mary Helen1, 1 Cell and Molecular Biology, Berkeley, CA
ABSTRACT-
The biological functions of active transforming growth factor- (TGF-) include the modulation of the enzymatic production of reactive oxygen species (ROS) such as superoxide anion and heme, as well as cell fate decisions in response to damage. The TGF- superfamily includes three mammalian isoforms (1, 2, and 3) that are secreted in a latent complex formed by non-covalent association with the relevant latency-associated peptide (LAP1, LAP2, or LAP3). Activation of TGF- involves dissociation of this complex and perhaps degradation of LAP. The sequence of the three TGF- isoforms is highly conserved (>97%). However the three LAP molecules exhibit a very little homology (>35%). The LAP sequence variations may suggest that different modes of activation are needed to release each TGF- dimer from the latent complex. We have demonstrated previously that latent TGF-1 (LTGF-1) is activated by ROS. By examining a panel of oxygen radical scavengers, we concluded that the hydroxyl radical appears to be critical for LTGF-1 activation. We postulate that the presence of metals (iron and copper) in the three-dimensional latent complex could provide a redox active center for this process. Given the LAP sequence differences we hypothesized that redox mediated activation will be isoform specific. Here we sought to further characterize and compare LTGF-1 and LTGF-2 susceptibility to activation under these conditions using assays to detect biologically active TGF-. Following exposure to FeIII-catalyzed ascorbate generated ROS, activation of LTGF1 was observed whereas LTGF2 remained in the inactive state. Redox mediated activation offers a novel route for TGF-1 involvement in chronic tissue processes in which oxidative stress is implicated and would endow latent TGF-1 with the ability to both sense extracellular oxidative stress and transduce the signal by eliciting changes in diverse cell types.
KEYWORDS: TGF, activation, reactive oxygen species, latency associated peptide