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This chapter aims to explain the functional impact of the proteasome activator (PA)28γ protein in cellular survival. The mechanistic complexity of this proteasome activator, encoded by the PSME3 gene and overexpressed in tumors in correlation with the degree of severity, is attracting growing attention. Taking anti-apoptotic properties of PA28γ into account, a simple view might explain therapy resistance of tumors by the presence of high concentrations of this proteasome regulator. A more sophisticated approach would consider functional parameters such as subcellular distribution, competition with other proteasome regulators, and factors affecting heptamer assembly, proteasome binding, and activation. Recently, PA28γ has been attributed as a proteasomal recognin, particularly for intrinsically unstructured proteins (IUPs), targeted by ubiquitin-independent proteasomal protein (UIPP) degradation. Other reports demonstrated inhibitory or stimulatory effects of PA28γ on turnover of substrates of the ubiquitinand ATP-dependent proteasome system (UPS). Since the understanding of functional implications of PA28γ on diverse signaling processes has grown exponentially and the orchestration of proteolytic systems within apoptosis is fairly complex, this article summarizes the recent developments in PA28γ biology with emphasis on cell survival signaling pathways such as DNA repair and apoptosis.

Proteasome Activator 28γ: Impact on Survival Signaling and Apoptosis