Alternatively spliced products CC3 and TC3 have opposing effects on apoptosis

The human gene CC3 is a metastasis suppressor for small cell lung carcinoma (SCLC) in vivo. The ability of CC3 to impair the apoptotic resistance of t umor cells is likely to contribute to metastasis suppression. We describe h ere an alternatively spliced RNA of CC3, designated TC3, that encodes an un stable protein with antiapoptotic activity, TC3 and CC3 proteins share amin o-terminal sequences, but TC3 has a unique short hydrophobic carboxyl termi nus. Overexpression of CC3 results in massive death of rodent fibroblasts, but TC3 protects cells from CC3-induced death and from other death stimuli such as treatment with tumor necrosis factor or overexpression of Bax prote in. The death-inducing activity of CC3 resides within its amino-terminal do main, which is conserved in TC3, The carboxyl terminus of TC3 is responsibl e for the antiapoptotic function of TC3; mutations in this domain abolish t he ability of TC3 to protect cells from apoptosis, TC3 protein is short-liv ed due to its rapid degradation by proteasome, and it forms complexes with a regulatory subunit of proteasome known as s5 alpha. The signal for the ra pid degradation of TC3 resides within its carboxyl terminus, which is capab le of conferring instability on a heterologous protein. The proapoptotic ac tivity of CC3 in SCLC cells is induced by a wide variety of signals and inv olves disruption of the mitochondrial membrane potential (Delta psi m). The CC3 protein has sequence similarity to bacterial short-chain dehydrogenase s/reductases and might represent a phylogenetically old effector of cell de ath similar to the recently identified apoptosis-inducing factor, CC3 and T C3 have opposing functions in apoptosis and represent a novel dual regulato r of cell death.