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J. Biol. Chem., Vol. 278, Issue 13, 11676-11685, March 28, 2003

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MTA1 Interacts with MAT1, a Cyclin-dependent Kinase-activating Kinase Complex Ring Finger Factor, and Regulates Estrogen Receptor Transactivation Functions^*

Amjad H. Talukder^§, Sandip K. Mishra^§, Mahitosh Mandal, Seetharaman Balasenthil, Sonal Mehta, Aysegul A. Sahin^¶, Christopher J. Barnes, and Rakesh Kumar

From the Departments of  Molecular and Cellular Oncology and ^¶ Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The transcriptional activity of estrogen receptor- is controlled by coregulators. MTA1 (metastasis-associated protein 1) represses estrogen receptor--driven transcription by recruiting histone deacetylases (HDACs) to the estrogen response element containing target gene chromatin in breast cancer cells. Using a yeast two-hybrid screen with the MTA1 C-terminal domain as bait, we identified MAT1 (ménage á trois 1) as an MTA1-binding protein. MAT1 is an assembly/targeting factor for cyclin-dependent kinase-activating kinase (CAK), which has been shown to functionally interact with general transcriptional factor TFIIH, a known inducer of ER transactivation. We show that estrogen signaling promotes nuclear translocation of MAT1 and that MTA1 interacts with MAT1 both in vitro and in vivo. MAT1 binds to the C-terminal 389-441 amino acids GATA domain and N-terminal 1-164 amino acids bromo-domain of MTA1, whereas MTA1 binds to the N-terminal ring finger domain of the MAT1. In addition, MAT1 interacts with the activation function 2 domain of ER and colocalizes with ER in activated cells. MTA1 deregulation in breast cancer cells led to its interactions with the CAK complex components, ER, and HDAC2. Accordingly, MTA1 inhibited CAK stimulation of ER transactivation that was partially relieved by HDAC inhibitor trichostatin A, suggesting that MTA1 might inhibit CAK-induced transactivation function of ER by recruiting HDAC. Furthermore, MTA1 overexpression inhibited the ability of CAK complex to phosphorylate ER. Together, these findings identified MAT1 as a target of MTA1 and provided new evidence to suggest that the transactivation functions of ER might be influenced by the regulatory interactions between CAK and MTA1 in breast cancer cells.

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