c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities

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Abstract

The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun. Following in vitro translation, c-Jun binds as a homodimer to the AP-1 DNA site, while c-Fos fails to dimerize and displays no apparent affinity for the AP-1 element. Cotranslated c-Jun and c-Fos proteins bind 25 times more efficiently to the AP-1 DNA site as a heterodimer than does the c-Jun homodimer. These experiments suggest that in growth factor-stimulated cells c-Jun binds DNA as a dimer with c-Fos as its natural partner. However, overexpression of c-Jun protein in the absence of c-Fos may result in formation of aberrant homodimeric transcription complexes, which could abrogate the normal mechanisms controlling gene expression.

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Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements.

Wes Lee, Pamela Mitchell, Robert Tjian (1987)

The enhancer-binding protein AP-1 has been purified to greater than 95% homogeneity from HeLa cells by sequence-specific DNA affinity chromatography and identified as a 47 kd polypeptide. Purified AP-1 activates transcription in vitro of the wild-type human metallothionein IIA (hMT IIA) gene but not mutant hMT IIA promoters lacking AP-1 recognition sites. DNAase I protection analysis indicates that genetically defined enhancer elements in hMT IIA, SV40, and the human collagenase gene contain high-affinity AP-1-binding sites, each with a conserved recognition motif, TGACTCA. These three genes are transcriptionally induced by treatment of cells with the tumor promoter TPA. Here we demonstrate that multiple synthetic copies of the consensus AP-1-binding site can act as TPA-inducible enhancers in various plasmid constructs after transfection into HeLa cells. These findings suggest that AP-1 is a transcription factor that functions by interacting with a specific enhancer element, and that its activities may be modulated by treatment of cells with TPA, known to stimulate protein kinase C.

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The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins.

Timothy Johnson, William H. Landschulz, Leslie L. McKnight (1988)

A 30-amino-acid segment of C/EBP, a newly discovered enhancer binding protein, shares notable sequence similarity with a segment of the cellular Myc transforming protein. Display of these respective amino acid sequences on an idealized alpha helix revealed a periodic repetition of leucine residues at every seventh position over a distance covering eight helical turns. The periodic array of at least four leucines was also noted in the sequences of the Fos and Jun transforming proteins, as well as that of the yeast gene regulatory protein, GCN4. The polypeptide segments containing these periodic arrays of leucine residues are proposed to exist in an alpha-helical conformation, and the leucine side chains extending from one alpha helix interdigitate with those displayed from a similar alpha helix of a second polypeptide, facilitating dimerization. This hypothetical structure is referred to as the "leucine zipper," and it may represent a characteristic property of a new category of DNA binding proteins.

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The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes.

Robert Chiu, William J. Boyle, Jennifer Meek … (1988)

Cell lines stably transfected with metal inducible, MT-fos chimeric genes were used to study the ability of the c-fos gene product, Fos, to act as a transcriptional trans-activator. In 3T3MTfos cells, induction of Fos expression led to specific trans-activation of an AP-1 responsive reporter gene. Induction of Fos expression in F9MTfos cells, however, did not lead to trans-activation. Since, unlike NIH3T3 cells, F9 cells do not contain detectable levels of AP-1, we examined whether a c-Jun/AP-1 expression vector can restore the trans-activating effect of Fos in F9MTfos cells. Transfection with a functional c-Jun/AP-1 vector restored the specific trans-activating effect of Fos on AP-1 responsive constructs. When incubated with nondenatured cell extracts, anti-cFos antisera precipitated a protein complex composed of Fos and several Fos associated proteins (FAP). One of these, FAP p39, is structurally identical to c-Jun/AP-1. These results suggest that Fos is a trans-acting factor that is capable of stimulating gene expression not by direct binding to DNA but by interaction with the sequence-specific transcription factor AP-1. Therefore recognition of specific cis-elements by AP-1 is a prerequisite for Fos-mediated stimulation of gene expression.