Mitra S, Sammani S, Wang T, Boone DL, Meyer NJ, Dudek SM, Moreno-Vinasco L, Garcia JG, Jacobson JR

RATIONALE: The stress-induced GADD45a (growth arrest and DNA damage-inducible alpha) gene is upregulated by mechanical stress with GADD45a knockout (GADD45a-/-) mice demonstrating both increased susceptibility to ventilator-induced lung injury (VILI) and reduced levels of the cell survival and vascular permeability signaling effector, Akt. However, the functional role of GADD45a in ...

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the pathogenesis of VILI is unknown. OBJECTIVES: We sought to define the role of GADD45a in the regulation of Akt activation induced by mechanical stress. Methods and RESULTS: Studies exploring the linkage of GADD45a with mechanical stress and Akt regulation revealed VILI-challenged GADD45a-/- mice to have significantly reduced lung injury upon over-expression of a constitutively-active Akt-1 transgene. Increased mechanical stress with 18% cyclic stretch in human endothelial cells (EC) induced Akt phosphorylation via E3 ligase TRAF6-mediated Akt K63 ubiquitination resulting in Akt trafficking and activation at the membrane. GADD45a is essential to this process as both GADD45a-silenced EC and GADD45a-/- mice exhibited increased Akt K48 ubiquitination leading to proteasomal degradation. These events involve loss of UCHL1, a deubiquitinating enzyme that normally removes K48 poly-ubiquitin chains bound to Akt thus promoting Akt K63 ubiquitination. Loss of GADD45a significantly reduces UCHL1 expression via UCHL1 promoter methylation resulting in increased Akt K48 ubiquitination and reduced Akt levels. CONCLUSION: These studies highlight a novel role for GADD45a in the regulation of site-specific Akt ubiquitination and activation and implicate a significant functional role for GADD45a in the clinical predisposition to VILI.

Date: Aug. 18, 2011

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