TRAF2 and TRAF5 are adapter proteins involved in TNF\#945;-induced activation of the JNK and NF-\#954;B pathways. Currently, TNF\#945;-induced NF-\#954;B activation is believed to be impaired in TRAF2 and TRAF5 double knockout (T2/5 DKO) cells. Here, we report instead that T2/5 DKO cells exhibit high basal IKK activity and elevated expression of NF-\#954;B-dependent genes in unstimulated conditions. Although TNF\#945;-induced RIP1 ubiquitination is indeed impaired in T2/5 DKO cells, TNF\#945; stimulation further increases IKK activity in these cells, resulting in significantly elevated expression of NF-\#954;B target genes to a level higher than that in wild-type cells. Inhibition of NIK in T2/5 DKO cells attenuates basal IKK activity and restores robust TNF\#945;-induced IKK activation to a level comparable to that seen in wild-type cells. This suggests that TNF\#945; can activate IKK in the absence of TRAF2 and TRAF5 expression and RIP1 ubiquitination. In addition, both the basal and TNF\#945;-induced expression of anti-apoptotic proteins are normal in T2/5 DKO cells, yet these DKO cells remain sensitive to TNF\#945;-induced cell death, due to the impaired recruitment of anti-apoptotic proteins to the TNFR1 complex in the absence of TRAF2. Thus, our data demonstrate that TRAF2 negatively regulates basal IKK activity in resting cells, and inhibits TNF\#945;-induced cell death by recruiting anti-apoptotic proteins to the TNFR1 complex rather than by activating the NF-\#954;B pathway.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5269.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO