CBP and histone deacetylase inhibition enhance the transactivation potential of the HOXB7 homeodomain-containing protein

Abstract

Homeodomain-containing proteins are transcription factors regulating the coordinated expression of multiple target genes involved in development, dierentiation and cellular transformation. In this study, we demonstrated that HOXB7, one member of this family, behaved as a transactivator in breast cancer cells. Deletion of either the HOXB7 N-terminal domain or the C-terminal acidic tail abolished this transcriptional eect, suggesting a combination of distinct functional transactivating domains. HOXB7 physically interacted both in vitro and in vivo with the coactivator CREB-binding protein (CBP). This interaction led to an enhanced transactivating potential and required the N-terminal of HOXB7 as well as two domains located at the C-terminal part of CBP. Moreover, trichostatin A, a deacetylase inhibitor, strongly enhanced the transcriptional properties of HOXB7. Our data therefore indicate that HOX proteins can directly interact with CBP and that acetylation/ deacetylation may regulate their transcriptional properties.

Pbx1 dependent control of VMC differentiation kinetics underlies gross renal vascular patterning

“…In the present study, we show Koss et al, 2012) and the osteoblast-related gene Osx (Sp7 -Mouse Genome Informatics) (Gordon et al, 2010). Notably, recent reports suggest the ability of Pbx to interact with and recruit co-repressors, including Hdac1 (part of the Sin3/NuRD/Co-REST regulatory complex) and Hdac3 (part of the NCoR/SMRT complex), which facilitate chromatin condensation by histone 3 deacetylation and nucleosome positioning (Asahara et al, 1999;Chariot et al, 1999;Saleh et al, 2000;Choe et al, 2009;Gordon et al, 2010). Thus, it is possible that similar mechanisms of Pbx1-dependent repression are used to regulate Pdgfrb transcription in the developing kidney.…”

Identification of Novel Functional Regions Important for the Activity of HOXB7 in Mammalian Cells

“…For example, Schnabel and Abate-Shen (36) deleted the glutamate-rich region and an additional 25 amino acids upstream of it from HOXA7, and observed a reduction in transcriptional repression of a reporter gene in transient transfection assays. More recently, a carboxyl-terminal deletion of HOXB7 was reported to cause reduced transcriptional activation of a reporter gene (37). This deletion spanned the glutamate-rich region, but also eliminated the CKII consensus target sequence at T204.…”

AP-1 complex is effector of Hox-induced cellular proliferation and transformation

“…Our inability to detect bona ®de Hox or Hox/Pbx DNA-binding sites in the proximal regulatory regions of Jun-B and Fra-1 suggests that Hoxb4 may regulate the expression of these transcription factors indirectly, possibly by attenuating the activity of upstream regulators of these two genes. There is also a growing body of evidence suggesting that Hox/Pbx dimers interact directly with CBP/p300 (Asahara et al, 1999;Chariot et al, 1999). This co-activator interacts with a number of proteins involved in regulation of cellular proliferation and survival, including CREB and AP-1 (Snowden et al, 1998), and could represent an adapter between the distal Hox/Pbx binding sites and ATF/CREB or AP-1 responsive regulatory elements, including Jun-B, Fra-1 and cyclin D promoters.…”