DLX5 (Distal-less Homeobox 5) Promotes Tumor Cell Proliferation by Transcriptionally Regulating MYC
ABSTRACT The human DLX homeobox genes, which are related to Dll (Drosophila distal-less gene), encode transcription factors that are expressed primarily in embryonic development. Recently, DLX5 was reported to act as an oncogene in lymphomas and lung cancers, although the mechanism is not known. The identification
of target genes of DLX5 can facilitate our understanding of oncogenic mechanisms driven by overexpression of DLX5. The MYC oncogene is aberrantly expressed in many human cancers and regulates transcription of numerous target genes involved in tumorigenesis.
Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian
cells. Furthermore, overexpression of DLX5 results in increased cell proliferation by up-regulating MYC. Knockdown of DLX5
in lung cancer cells overexpressing DLX5 resulted in decreased expression of MYC and reduced cell proliferation, which was
rescued by overexpression of MYC. Because DLX5 has a restricted pattern of expression in adult tissues, it may serve as a
potential therapeutic target for the treatment of cancers that overexpress DLX5.
- SourceAvailable from: Andrea Streit
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- "Already before gastrulation, the non-neural ectoderm expresses transcription factors of the Ap2 (Hoffman et al., 2007; Knight et al., 2003, 2005; Li and Cornell, 2007; Luo et al., 2003; Werling and Schorle, 2002; see review: Eckert et al., 2005), Foxi (Foxi1 in fish (Solomon et al., 2003a) and Xenopus (Matsuo-Takasaki et al., 2005; see review: Pohl and Knochel, 2005; Pohl et al., 2002; Suri et al., 2005); Foxi3 in mouse (Ohyama and Groves, 2004), Gata2 and -3 (Dirksen et al., 1994; Neave et al., 1995; Sheng and Stern, 1999) and Dlx families (Dlx3/4 in teleost (Solomon and Fritz, 2002), Dlx5/6 in amniotes (Brown et al., 2005; Davideau et al., 1999; McLarren et al., 2003; Quint et al., 2000; Simeone et al., 1994; Stock et al., 1996; Zhang et al., 1997; see review: Kraus and Lufkin, 1999; Merlo et al., 2000) or Dlx3/5 in Xenopus (Akimenko et al., 1994; Dirksen et al., 1993; Luo et al., 2001a,b; Woda et al., 2003). These are activated downstream of BMP signalling (Beanan and Sargent, 2000; Luo et al., 2001b; Mir et al., 2007; Pohl and Knochel, 2005; Suri et al., 2005; see review: Xu and Testa, 2009) prior to the onset of Six1/4 and Eya1/2 and are cell autonomously required for the activation of their expression (Kwon et al., 2010; Pieper et al., 2012). In Xenopus, ectopic Dlx3 or Gata2 expression broadens Six1 and Eya2, while repressing the neural marker Sox3 and the neural crest markers Msx1, Pax3 and Zic1. "
ABSTRACT: Despite its complexity in the adult, during development the inner ear arises from a simple epithelium, the otic placode. Placode specification is a multistep process that involves the integration of various signalling pathways and downstream transcription factors in time and space. Here we review the molecular events that successively commit multipotent ectodermal precursors to the otic lineage. The first step in this hierarchy is the specification of sensory progenitor cells, which can contribute to all sensory placodes, followed by the induction of a common otic-epibranchial field and finally the establishment the otic territory. In recent years, some of the molecular components that control this process have been identified, and begin to reveal complex interactions. Future studies will need to unravel how this information is integrated and encoded in the genome. This will form the blueprint for stem cell differentiation towards otic fates and generate a predictive gene regulatory network that models the earliest steps of otic specification.Hearing research 11/2012; 297. DOI:10.1016/j.heares.2012.11.018 · 2.85 Impact Factor
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ABSTRACT: Akt plays a central role in regulating tumor cell survival and cell cycle progression and is regarded as a promising therapeutic target. We used genetically defined mouse models that develop spontaneous tumors exhibiting activated Akt to determine if Akt inhibition by GSK690693 is effective in the treatment of cancer. The broad long-term objective of this project was to use preclinical cancer models with precisely defined genetic lesions to elucidate the efficacy of targeting Akt with GSK690693. We tested the in vivo effects of GSK690693 in Lck-MyrAkt2 transgenic mice that develop lymphomas, heterozygous Pten(+/-) knockout mice that exhibit endometrial tumors, and TgMISIIR-TAg-DR26 mice that develop ovarian carcinomas, all of which exhibit hyperactivation of Akt. In addition to standard disease onset and histology, tumors arising in treated animals were examined by immunohistochemistry to verify downregulated Akt signaling relative to placebo-treated mice. When possible, drug response was evaluated in tumor cell cultures by standard proliferation and apoptosis assays and by immunoblotting with various phosphospecific antibodies. GSK690693 exhibited efficacy irrespective of the mechanism of Akt activation involved. Interestingly, GSK690693 was most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. Both tumors and primary cell cultures displayed downregulation of the Akt pathway, increased apoptosis, and primarily decreased cell proliferation. These results suggest that GSK690693 or other Akt inhibitors might have therapeutic efficacy in human cancers with hyperactivated Akt and/or a dependence on Akt signaling for tumor progression.Clinical Cancer Research 01/2010; 16(2):486-96. DOI:10.1158/1078-0432.CCR-09-1026 · 8.19 Impact Factor
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ABSTRACT: The crystal structure of the human transcription factor DLX5 has been used for the screening of a library consisting of 106 compounds by the molecular docking technique.In vitro testsof the 14 top-rated ligands showed that compound Q12 displays the best ability to inhibit the proliferation ofDlx5 positive mouse lymphoma cells, which correlates with the down-regulation ofc-mycexpression. Compound Q12 has low toxicity on normal human ovarian epithelial cells and mouse lymphoma cells with absent expression ofDlx5, and can be used for further chemical optimization and for the development of novel, highly efficient cancer treatments.07/2011; 3(3):47-51.