Dr Salvatore Papa

During the past few years, my efforts have been directed towards the identification and characterization of the downstream effectors of the prosurvival activity of NF-kappaB.  My primary focus was to uncover a mechanism by which Gadd45{beta}, a downstream effector of NF-kappaB, blunt JNK signalling. We have identified the MAPKK MKK7/JNKK2 – a specific and essential activator of JNK – as a target of Gadd45{beta}, and in fact, of NF-kappaB itself. Gadd45{beta} associates directly and tightly with MKK7, inhibiting its catalytic activity, and this inhibition is central to the Gadd45-mediated suppression of TNF-induced JNK signalling and apoptosis (Papa S. et al., Nat Cell Biol, 2004). Subsequently, we have defined the precise mechanism by whichGadd45{beta} blocks MKK7, and ultimately, TNF-induced programmed cell death (Papa S., et al., J Biol Chem, 2007). These findings identify the MKK7-Gadd45{beta} interaction as a potential new target for anti-inflammatory and anti-cancer therapy. Interestingly, pharmacological compounds that disrupt Gadd45{beta} binding to MKK7 might uncouple anti-apoptotic and proinflammatory functions of NF-kappaB, and so, circumvent the potent immunosuppressive side effects of global blockers of NF-kappaB.  

To understand the physiological contexts in which Gadd45{beta} blocks the JNK activity, I then generated and analyzed Gadd45{beta}-null mice. Analyses of these mice revealed that Gadd45{beta} is required for liver regeneration, and the regenerative response is associated with selective attenuation of JNK2 isoform. These findings have important implications for treatment of widespread liver diseases (Papa S et al., J Clin Invest, 2008; Papa S. et al., Biol Chem. 2009).

 

Selected publications:

Papa S; Bubici C; Zazzeroni F; Franzoso G. (Oct 2009). Mechanisms of liver disease: cross-talk between the NF-kappaB and JNK pathways. Biol Chem. 390:965-976.

 

Papa S; Zazzeroni F; Fu YX; Bubici C; Alvarez K; Dean K; Christiansen PA; Anders RA; et al. (May 2008). Gadd45 beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. J CLIN INVEST. 118:1911-1923.

 

Papa S; Monti SM; Vitale RM; Bubici C; Jayawardena S; Alvarez K; De Smaele E; Dathan N; et al. (2007). Insights into the structural basis of the Gadd45{beta}-mediated inactivation of the JNK Kinase, MKK7/JNKK2. J Biol Chem. 282:19029-19041.

 

Papa S; Zazzeroni F; Bubici C; Jayawardena S; Alvarez K; Matsuda S; Nguyen DU; Pham CG; et al. (Feb 2004). Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. NAT CELL BIOL. 6:146-153.

 

Zazzeroni F; Papa S; De Smaele E; Franzoso G. (14 Aug 2003). Cell signalling (communication arising) - Cell survival and a Gadd45-factor deficiency. NATURE. 424:742-742.

 

De Smaele E; Zazzeroni F; Papa S; Nguyen DU; Jin R; Jones J; Cong R; Franzoso G. (15 Nov 2001). Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature. 414:308-313.