Tip60 Is a Co-activator Specific for Class I Nuclear Hormone Receptors

Abstract

The nuclear hormone receptor superfamily is composed of a group of hormone-dependent transcription factors that play prominent roles in homeostatic events in vertebrates. A prerequisite for steroid hormone receptor activity is the binding of co-activator molecules to the activation function-2 domain of the receptor. The LXXLL motif/nuclear receptor box, contained within a number of co-activator molecules, mediates the interaction with nuclear hormone receptors. Tip60 (Tat-interactive protein 60 kDa), previously shown to bind to and enhance androgen receptor (AR)-mediated transactivation, contains a single nuclear receptor box at its extreme C terminus. We demonstrate that unlike members of the p160 co-activator family that interact predominantly with the N terminus of the AR in an LXXLL motifindependent manner, the LXXLL motif of Tip60 is required and is sufficient for AR interaction. Furthermore, by using the mammalian two-hybrid system and transient transfection experiments, we show that Tip60 preferentially interacts with and up-regulates class I nuclear receptors, suggesting that Tip60 is a steroid hormone receptor-specific co-activator. We conclude that Tip60 may specifically regulate a subset of nuclear hormone receptors, giving an indication to how regulated nuclear receptor activation can be achieved.The androgen receptor (AR), 1 a member of the steroid hormone receptor family, is a ligand-inducible transcription factor that plays a key role in the growth, development, and transformation of the prostate gland (1, 2). The AR, in common with other members of the nuclear hormone receptor (NR) family, is a modular protein containing distinct functional domains (for review, see Ref.3). DNA interaction involves the centrally positioned double zinc finger-containing DNA-binding domain (DBD) (4, 5), which is highly conserved throughout the family of nuclear receptors (NR). Hormone binding is performed by the C-terminal ligand-binding domain (LBD), a structurally conserved region within the family of NRs, containing 12 ␣-helices (H1-H12) (6 -8), which in addition mediates homodimerization and plays a role in transcriptional activation. This latter function is performed by the extreme C-terminal helix H12 of the LBD, termed activation function-2 (AF-2) (9), a ligand-dependent transcriptional activator which, in combination with the N-terminal transactivation domain (TD), is able to activate receptor-mediated gene expression. Although not fully defined, the AF-2 domain of NRs has been proposed to mediate direct interactions with a number of co-activator proteins necessary for the full transcriptional activity of the receptor (8, 10). To date, numerous co-activator molecules have been characterized, such as members of the p160 family, including SRC-1 (steroid receptor co-activator-1) (11) and GRIP-1 (glucocorticoid receptor-interacting protein-1) (12); the CREB-binding protein (CBP)/p300 proteins (13, 14) and p300/CBP-associating factor (15). The finding that many of these co-activator molecules are histone acetyltr...

The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways

“…In agreement with its function in histone acetylation, Tip60 is mainly involved in transcriptional activation of specific genes (Gaughan et al, 2001;Berns et al, 2004;Legube et al, 2004). Transcriptional regulation of some genes, such as E2F or c-mycdependent genes, most likely involves the whole Tip60 complex (Frank et al, 2003;Taubert et al, 2004).…”

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

“…Tip60 enhances ER␣ transactivation at ERE sites in a ligand-dependent manner (29,30) and thus increases the expression of certain ER␣ target genes (29,31). A study also shows that Tip60 interacts with ER␤1 in the presence of estrogen (32). However, it remains unclear how Tip60 modulates ER␤1 function.…”

Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development

“…We previously identified Tat interactive protein, 60 kDa (Tip60) as an AR coactivator and showed that it potentiates AR transcriptional activity both in vitro and in vivo (Brady et al, 1999). We further demonstrated that Tip60 is a coactivator specific for Class I nuclear hormone receptors, including oestrogen and progesterone receptor (Gaughan et al, 2001). Tip60 is a histone acetyltransferase belonging to the MYST protein family (Yamamoto and Horikoshi, 1997).…”