Analysis ofAP-1Function inCellular Transformation Pathways

(FBJ) murine sarcoma virus (11) and avian sarcoma virus 17(21), respectively. c-fos belongs toa multigene family thatincludesfra-1 (9),fra-2 (23, 27), andfosB (42), andthefosgenefamily codesfornuclear proteins that dimerize withtheJunfamily proteins, suchasc-Jun (26), JunB (33), andJunD(16,32),toformthetranscription factor complex AP-1.Dimerization occursspecifically through a leucine zipper structure: Junfamily memberscanformlowaffinity homodimers andhigh-affinity heterodimers withthe Fosfamily, whereas Fos-related proteins donotformstable homodimers (10, 25). Although these hetero- andhomodimers bindtosimilar DNA-binding sites (TGACTCA, AP-1-binding sites) through thebasic domains ofbothproteins, whichare juxtaposed bythedimerization, eachdimer wasshowntohave adistinct transcriptional regulatory function, sothat transcription canbepositively andnegatively modulated (37). High-level expression ofmostmembersofthefosorjun genefamily hasbeenreported tocause cellular transformation ofchicken embryo fibroblasts (CEF)(17, 27,36). JunDhasno transforming activity, butitcanacquire transforming potential byspontaneous mutation (15, 18). Theseresults indicate that uncontrolled expression andqualitative change ofanycomponentofAP-1caninduce cellular transformation. Logarithmically growing CEF express c-JunandFra-2at relatively highlevels (36, 41), andbasal-level expression of