Tip60 Is a Co-repressor for STAT3

Abstract

Tip60 (Tat-interactive protein, 60 kDa), a cellular protein with intrinsic histone acetyltransferase activity, is involved in DNA damage repair and apoptosis. Recent studies have suggested that Tip60 acts either as a coactivator or a co-repressor to modulate transcription. In this study, we demonstrate that Tip60 represses reporter gene expression when it is fused to the Gal4 DNA binding domain. We also show that Tip60 associates with histone deacetylase 7 (HDAC7) through its N-terminal zinc finger-containing region and that HDAC7 activity is required for the repressive effect of Tip60. Because endogenous Tip60 interacts with STAT3, we hypothesized that Tip60 might complex with STAT3 and HDAC7 and modulate STAT3-mediated trans-activation. Consistent with this hypothesis, the overexpression of Tip60 represses STAT3-driven reporter gene expression, which can be further potentiated by the co-transfection of HDAC7. Furthermore, interleukin-9-induced c-myc expression, which depends on STAT3 activity, is abrogated by exogenous expression of Tip60. This is the first demonstration of which Tip60 represses STAT3 activity in part through the recruitment of HDAC7. Tip601 (Tat-interactive protein, 60 kDa) is a member of the MYST family of proteins, which are highly conserved from yeast to human and play diverse physiological functions (1). Several members among this family, such as SAS3 (Something About Silencing), Esa1 (Essential sas2-related acetyltransferase), and Tip60, possess intrinsic histone acetyltransferase (HAT) activity (2-4), suggesting their potential roles in chromatin remodeling and gene regulation. Tip60 is expressed in a variety of tissues and cell lines, and its homologues have been identified in chicken, mouse, and human (5-7). Tip60 is mainly localized in the nucleus; however, cytoplasmic and perinuclear localization has been reported previously (4, 8 -11). Tip60 forms stable nuclear complexes, which possess ATPase and DNA helicase activities, that promote histone acetylation in nucleosomes (12). It associates with transcriptional activators, such as HIV-1 Tat, type I nuclear hormone receptors, and APP (␤-Amyloid Precursor Protein), to activate gene expression (7,13,14). Tip60 has also been implicated in the negative regulation of gene expression through binding to CREB or the transcriptional repressor ZEB (Zinc Finger E Box-binding Protein) (15,16). Interestingly, Tip60 interacts with membrane receptors for IL-9 and endothelin (10, 11), suggesting its involvement in signal transduction in response to extracellular stimuli. Cytosolic phospholipase A2-interacting protein, a differentially spliced form of Tip60, interacts with cytosolic phospholipase A2 to enhance cytosolic phospholipase A2-mediated cell death and prostaglandin E2 production (9).Eucaryotic genomic DNA is packaged with histones into nucleosomes, which are the primary structural units of chromatin. The packaging of DNA into chromatin inhibits transcription in part by hindering the binding of transcription factors and basal transcriptional m...

Widespread regulation of gene expression in the Drosophila genome by the histone acetyltransferase dTip60

“…In humans, there is evidence that hTip60 acts in a complex with a histone deacetylase, which mediates a repressive function (Ai et al, 2007;Xiao et al, 2003). Therefore, we hypothesized that in Drosophila, dTip60 might also work with an HDAC to repress distinct genes.…”

“…While this may not require its HAT activity, Tip60 interaction with the DNA binding factors STAT3 and KLF4 serves to recruit the histone deacetylase HDAC7 to gene promoters, which causes gene repression (Ai et al, 2007;Xiao et al, 2003).…”

“…For example, hTip60 was found to act as a corepressor by recruitment of HDAC7 (Xiao et al, 2003) and represses HDC promotor activity together with KLF4 and HDAC7 (Ai et al, 2007).…”

Class IIa histone deacetylases: regulating the regulators

“…During the past few years, class IIa HDACs have been shown to repress an increasing number of transcriptional regulators through direct or indirect interaction. Interestingly, many of these are important regulators of key genetic programs during development, such as members of the GATA (Ozawa et al, 2001;Watamoto et al, 2003), Forkhead (Li et al, 2007), NK-2 homeodomain-containing and signal transducer and activator of transcription (Xiao et al, 2003) families of transcription factors.…”

STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

“…Because Gsk-3␤ is a constitutively active gene and because expression of Gsk-3␤ does not require an enhancer, STAT3 plays a relatively logical role in regulating Gsk-3␤ as a suppressor. In addition, STAT3 may recruit cofactors to determine whether to activate or repress a downstream gene (18,35). Although STAT3 sometimes plays different roles in biological events, the ultimate biochemical effect of activated STAT3 seems to lie in its ability to increase or decrease the transcriptional activity of previously quiescent or active genes.…”