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J. Biol. Chem., Vol. 280, Issue 11, 10119-10127, March 18, 2005

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MEIS C Termini Harbor Transcriptional Activation Domains That Respond to Cell Signaling^*

He Huang, Mojgan Rastegar, Caroline Bodner, Siew-Lee Goh, Isabel Rambaldi, and Mark Featherstone¶

From the McGill Cancer Centre, McGill University, Montréal, Québec H3G 1Y6, Canada

MEIS proteins form heteromeric DNA-binding complexes with PBX monomers and PBX·HOX heterodimers. We have shown previously that transcriptional activation by PBX·HOX is augmented by either protein kinase A (PKA) or the histone deacetylase inhibitor trichostatin A (TSA). To examine the contribution of MEIS proteins to this response, we used the chromatin immunoprecipitation assay to show that MEIS1 in addition to PBX1, HOXA1, and HOXB1 was recruited to a known PBX·HOX target, the Hoxb1 autoregulatory element following Hoxb1 transcriptional activation in P19 cells. Subsequent to TSA treatment, MEIS1 recruitment lagged behind that of HOX and PBX partners. MEIS1A also enhanced the transcriptional activation of a reporter construct bearing the Hoxb1 autoregulatory element after treatment with TSA. The MEIS1 homeodomain and protein-protein interaction with PBX contributed to this activity. We further mapped TSA-responsive and CREB-binding protein-dependent PKA-responsive transactivation domains to the MEIS1A and MEIS1B C termini. Fine mutation of the 56-residue MEIS1A C terminus revealed four discrete regions required for transcriptional activation function. All of the mutations impairing the response to TSA likewise reduced activation by PKA, implying a common mechanistic basis. C-terminal deletion of MEIS1 impaired transactivation without disrupting DNA binding or complex formation with HOX and PBX. Despite sequence similarity to MEIS and a shared ability to form heteromeric complexes with PBX and HOX partners, the PREP1 C terminus does not respond to TSA or PKA. Thus, MEIS C termini possess transcriptional regulatory domains that respond to cell signaling and confer functional differences between MEIS and PREP proteins.

Received for publication, December 13, 2004 , and in revised form, January 11, 2005.

^* This work was funded by Operating Grant 38058 (to M. F.). from the Canadian Institutes of Health Research (CIHR). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of an Alexander McFee Scholarship and an Internal Scholarship from Faculty of Medicine, McGill University. Present address: En-470, 300 Longwood Ave., Division of Neuroscience, Children's Hospital, Boston, MA 02115.

Supported by CIHR Cancer Consortium Training Awards from the McGill Cancer Centre.

^¶ A Chercheur-National of the Fonds de la Recherche en Santé du Québec. To whom correspondence should be addressed: McGill Cancer Centre, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-8937; Fax: 514-398-6769; E-mail: mark.featherstone{at}mcgill.ca.

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