Exip, a new alternative splicing variant of p38α, can induce an earlier onset of apoptosis in HeLa cells

One of the major families of the mitogen-activated kinases (MAPK), p38, has been shown to transduce extracellular stress stimuli into cellular responses. Among them, p38a is the best characterized isoform and many biological phenomena, especially in the inflammatory responses, were attributed to the specific inhibitor-sensitive isoforms, namely p38a and p38beta. However, the roles played by each member are still unclear. Here, we report the identification of a new splice variant of p38alpha, Exip (for exon skip), by RT-PCR using mRNA derived from a renal tumor cell line, OS-RC-2. Exip is predicted to encode a 307-amino-acid protein and the absence of exons 10, 11, and 11' results in the shift of the reading frame at the exon 9-12 junction to produce a unique 53-amino-acid C-terminus. The expression of mRNA was barely observed in cultured cells tested, but substantial amounts of mRNA were detected in mouse tissues. Unlike p38a, Exip lost a common docking domain well conserved in major MAPK families for their specific interactions with upstream kinases or downstream substrates. Even though Exip is not phosphorylated at conserved TGY motif by p38-activating treatments, such as an osmotic shock or coexpression with a constitutive active form of MKK6 in HeLa cells, Exip can induce an earlier onset of apoptosis in HeLa cells. These results indicate that Exip has unique properties as a member of p38a and may play role(s) in the signal transduction pathway(s) different from those of p38alpha. (C) 2002 Elsevier Science (USA)