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GSK-3 Promotes Conditional Association of CREB and Its Coactivators with MEIS1 to Facilitate HOX-Mediated Transcription and Oncogenesis

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cancer cell (Impact Factor: 23.89). 06/2010; 17(6):597-608. DOI: 10.1016/j.ccr.2010.04.024
Source: PubMed

ABSTRACT Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias.

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Available from: Francesca Ficara, Mar 13, 2014
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    • "Tosedostat down regulated five of nine enriched genes in the V$E2F_01 promoter motif signature in HL-60 cells (acute promyelocytic leukemia) (Krige et al., 2008) where down regulation of MYC could impact a large number of TN enriched genes. The SB216763 inhibitor of GSK3Beta treatment of RS4;11 human leukemia cell line, down regulated 474 genes at least 1.5 fold that were significantly enriched for genes related to cell cycle and MYC-regulated genes (Wang et al., 2010). Knockout experiments of TLX and BMP2 indicate a down regulation of V$E2F_01, KTGGYRSGAA_UNKNOWN and V$E2F_Q3 enriched genes implicating them as possible therapeutic targets (Lee et al., 2007; Zhang et al., 2008). "
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    • "While all of these leukemias are molecularly distinct and have different etiologies, it is curious to note the connection between Gsk-3 activity, DNA methylation, and Hoxa gene expression that is common to ALL, CLL, MLL, and AML. Recent mechanistic studies on MLL suggests that regulation of MEIS1 activity via Gsk-3-dependent control of CREB, TORC, and CBP could represent a common molecular link between these disparate cancers (Wang et al., 2010). "
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    • "In contrast, the RA, GSK-3 and/or PKA pathways might act by means of Meis proteins to create an activating complex . In particular, RA induces Meis expression (Oulad-Abdelghani et al., 1997), while both PKA and GSK-3 signaling promotes CBP-mediated transcriptional activation by means of the Meis C-terminus (Huang et al., 2005; Goh et al., 2009; Wang et al., 2010). Hence, the end result of the conversion process would be displacement of co-repressors and recruitment of coactivators . "
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