A summarized scheme for Hyal-2-induced TNF susceptibility in L929 cells. Upregulation of proapoptotic WOX1 but not p53 was observed in the Hyal-2-expressing cells. Unlike PH-20, Hyal-2 could not induce constitutive JNK activation. TNF cytotoxicity was enhanced in these Hyal-2-expressing cells. The enhancement of TNF function is likely due to 1) the induced proapoptotic WOX1, 2) the likely translocation of Hyal-2 to the mitochondria in response to TNF, and 3) the prolonged period of IκBα degradation and NF-κB activation in as mediated by TNF.