Abstract
Our previous study shows that inhibiting activator protein one (AP1) transcription factor function in murine epidermis, using dominant-negative c-jun (TAM67), increases cell proliferation and delays differentiation. To understand the mechanism of action, we compare TAM67 impact in mouse epidermis and in cultured normal human keratinocytes. We show that TAM67 localizes in the nucleus where it forms TAM67 homodimers that competitively interact with AP1 transcription factor DNA binding sites to reduce endogenous jun and fos factor binding. Involucrin is a marker of keratinocyte differentiation that is expressed in the suprabasal epidermis and this expression requires AP1 factor interaction at the AP1-5 site in the promoter. TAM67 interacts competitively at this site to reduce involucrin expression. TAM67 also reduces endogenous c-jun, junB and junD mRNA and protein level. Studies with c-jun promoter suggest that this is due to reduced transcription of the c-jun gene. We propose that TAM67 suppresses keratinocyte differentiation by interfering with endogenous AP1 factor binding to regulator elements in differentiation-associated target genes, and by reducing endogenous c-jun factor expression.
Highlights
Activator protein one (AP1) transcription factors are a family of jun and fos proteins that form jun-jun and jun-fos homo- and heterodimers, and these complexes interact with AP1 factor DNA binding sites to regulate gene expression [1,2,3,4]
The level of c-jun, junB and junD encoding mRNA is reduced in TAM67 expressing cells, indicating that part of the reason for loss of these factors is a reduction in mRNA level (Fig. 2B)
We examined the ability of TAM67-FLAG to interact with other AP1 factors by testing the ability of TAM67-FLAG to co-precipitate individual AP1 factors in keratinocytes
Summary
Activator protein one (AP1) transcription factors are a family of jun and fos proteins that form jun-jun and jun-fos homo- and heterodimers, and these complexes interact with AP1 factor DNA binding sites to regulate gene expression [1,2,3,4]. The AP1 factor family includes c-jun, junB, junD, c-fos, FosB, Fra-1 and Fra-2. These proteins are implicated in control of keratinocyte proliferation [5,6,7], differentiation [8,9,10], apoptosis [11,12], and transformation [13,14,15,16]. An altered form of c-jun, which is truncated to remove the Nterminal transactivation domain, has been used to study AP1 factor function [26]. Deletion of the c-jun transactivation domain creates a dominant-negative form of the protein (TAM67) that inhibits AP1 factor function [26]. Inhibition of AP1 factor function in neuroblastoma cells suppresses nerve growth factor-dependent differentiation [32]
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