title: MEIS C termini harbor transcriptional activation domains that respond to cell signaling.
abstract: 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.
authors.affiliation: McGill Cancer Centre, McGill University, 3655 Promenade Sir William Osler, Montréal, Québec H3G 1Y6, Canada.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Mojgan
authors.initials: M
authors.lastname: Rastegar
authors.forename: Caroline
authors.initials: C
authors.lastname: Bodner
authors.forename: Siew-Lee
authors.initials: SL
authors.lastname: Goh
authors.forename: Isabel
authors.initials: I
authors.lastname: Rambaldi
authors.forename: Mark
authors.initials: M
authors.lastname: Featherstone
mesh_terms: D000409:Alanine / Q000737:chemistry; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D004791:Enzyme Inhibitors; C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C012589:trichostatin A; D004247:DNA; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases; D000409:Alanine