Transcription factors: a new family gathers at the cAMP response site

lloMMENT Transcription factors: a new family gathers at the cAMP response site Promoters for RNA polymerase II are subject to a bewildering array of controls. Nonetheless, success in tracking transcription control path­ways has advanced dramatically through the identification of tran­scription factors that associate with specific promoter elements and mediate the transcriptional re­·sponse to cellular regulatory sig­nals. One advance came with the discovery that the serum-inducible transcription factors Fos and Jun associate with one another to form a heterodimeric complex that is member of the AP-1 transcription factor family and binds to the con­sensus AP-1-binding site sequence 5'-GTGAGT(A/C)A-3' (the TPA re­sponse element or TRE; reviewed in Ref. 1). Other progress came from studies of the cAMP response el­ement (CRE) 5'-GTGACGTA/CA/G-3' (Ref. 2) and the closely related 'activation transcription factor' site (ATF site)3. These elements differ from the TRE by the insertion of a central C residue. A new report from the lab of Michael Green at Harvard4 suggests that the CRE/ ATF site binds a family of factors with much in common with the Fos-Jun family. These families may serve as paradigms for other transcription factor families and may provide novel mechanisms of gene control. Control of transcription factor activity through dimerization The Fos and Jun families pro­vide the best characterized ex­ample of transcription factors that use dimerization to control func­tion. A distinctive feature of Fos and Jun is their interaction through the hydrophobic faces of two amphipathic a.-helices, one on Fos and the other on Jun (reviewed in Ref. 1). The hydrophobic face of each helix is characterized by the presence of 4-5 leucine residues spaced at intervals of seven amino acids along the chain. The helices interact in parallel arrangement EDWARD B. ZIFF DEPARTMENT OF BIOCHEMISTRY, NEW YORK UNIVERSITY MEDICAL CE'JTER, 550 FIRST AVE'JUE, NEW YORK, NY 10012, USA. through the interdigitation of leucine hydrophobic side chains to form a 'leucine zipper', a structure first proposed by Landschulz et af.S for the homodimerization interface the transcription factor C/EBP. More recently, O'Shea et a/.6 have suggested that the zipper assumes a 'coiled-coil' structure, in which additional hydrophobic amino acids present in a '4-3 repeat' stabi­lize binding. With Fos and Jun, 'zipping' juxtaposes basic amino acid sequences from each peptide, which cooperate to bind to the TRE sequence in DNA (see ref­erences in Ref. 1). Vinson et a/.7 have incorporated the coiled-coil structure into a 'scissors grip model' for the zipper which the basic amino acid sequences are Fos-Jun Family: TRE present in a.-helical continuations of the zipper helices, which are wrapped around the DNA helix at the TRE. This model closely juxta­poses the basic amino acid sequences from Fos and Jun accounts for binding of the Fos-Jun heterodimer to the 'directly abutted' dyad symmetric DNA sequences found in the palindromic TRE. The model also explains the obser­vation that molecules that are unable to dimerize cannot bind DNA. The DNA-binding domain requires structural contributions from both subunits of the dimer. The zippers confer high speci­ficity for dimerization (reviewed in Ref. 1). Thus, the Fos zipper avidly binds to the Jun zipper but does not bind to itself nor the zippers ATF-CREB Family: ATF Site FICO Formation of heterodimeric and homodimeric complexes between Fos Jun family me'llbers and members of the ATF family transcription factors and association with DNA. Members of the Jun family can weakly homodimerize or form stronger heterodimeric complexes with Fos family members. members do not self-associate. The different dimers bind equivalently to TRE elements in DNA. Because effector domains differ, different complexes with DNA may have transcription regulatory properties. With the ATF-CREB family, dimerization rules appear to be more complex. The indicated dimers are permitted and these all bind to ATF sites DNA. TIG MARCH 1990 VOL. 6 NO. 3 ©1990 Elsevier Science Publishers Ltd (UK) OJ6H · 9479/90/S02.00