ArticleThe Journal of biological chemistry2007
The homeobox gene GAX activates p21WAF1/CIP1 expression in vascular endothelial cells through direct interaction with upstream AT-rich sequences.
Article in The Journal of biological chemistry, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
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- Molecular Signature of Tumor-Associated High Endothelial Venules That Can Predict Breast Cancer Survival.Cancer immunology research · 2022Article
- Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1.Human molecular genetics · 2022Article
- The putative CJournal of microbiology (Seoul, Korea) · 2020Article
- Mesenchyme Homeobox 2 Enhances Migration of Endothelial Colony Forming Cells Exposed to Intrauterine Diabetes Mellitus.Journal of cellular physiology · 2017Article
- Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents.Journal of stroke · 2017Review
- The homeoprotein DLX4 controls inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer.Molecular cancer · 2015Article
- Human miR-221/222 in Physiological and Atherosclerotic Vascular Remodeling.BioMed research international · 2015Review
- Growth arrest-specific homeobox is associated with poor survival in patients with hepatocellular carcinoma.Medical oncology (Northwood, London, England) · 2012Article
- miRNAs involved in the generation, maintenance, and differentiation of pluripotent cells.Journal of molecular medicine (Berlin, Germany) · 2012Review
- miRNA screening reveals a new miRNA family stimulating iPS cell generation via regulation of Meox2.EMBO reports · 2011Article
- The inhibitory effects of 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone on human colon cancer cells.Molecular nutrition & food research · 2011Article
- Mechanisms of MEOX1 and MEOX2 regulation of the cyclin dependent kinase inhibitors p21 and p16 in vascular endothelial cells.PloS one · 2011Article
- Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors.Journal of experimental & clinical cancer research : CR · 2010Article
- MEOX2 regulates nuclear factor-kappaB activity in vascular endothelial cells through interactions with p65 and IkappaBbeta.Cardiovascular research · 2010Article
- Regulation of the expression and activity of the antiangiogenic homeobox gene GAX/MEOX2 by ZEB2 and microRNA-221.Molecular and cellular biology · 2010Article
- Role of specific microRNAs for endothelial function and angiogenesis.Biochemical and biophysical research communications · 2009Review
- Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors.Journal of neuro-oncology · 2009Article
- Micromanaging vascular biology: tiny microRNAs play big band.Journal of vascular research · 2009Review
- A functional screen for regulators of CKDN2A reveals MEOX2 as a transcriptional activator of INK4a.PloS one · 2009Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Tumors secrete pro-angiogenic factors to induce the ingrowth of blood vessels from the surrounding stroma, the end targets of which are vascular endothelial cells (ECs). The homeobox gene GAX inhibits angiogenesis and induces p21(WAF1/CIP1) expression in vascular ECs. To elucidate the mechanism through which GAX activates p21(WAF1/CIP1) expression, we constructed GAX cDNAs with deletions of the N-terminal domain, the homeodomain, or the C-terminal domain and then assessed these constructs for their ability to activate p21(WAF1/CIP1). There was an absolute requirement for the homeodomain, whereas deleting the C-terminal domain decreased but did not abolish transactivation of the p21(WAF1/CIP1) promoter by GAX. Deleting the N-terminal domain did abolish transactivation. Next, we performed chromatin immunoprecipitation and found, approximately 15 kb upstream of the p21(WAF1/CIP1) ATG codon, an ATTA-containing GAX-binding site (designated A6) with a sequence similar to that of other homeodomain-binding sites. GAX was able to bind to A6 in a homeodomain-dependent manner and thereby activate the expression of a reporter gene coupled to this sequence, and this activation was abolished by mutating specific residues in this sequence. On the basis of the sequence of A6, we were then able to locate other ATTA-containing sequences that also bound GAX and activated transcription in reporter constructs. Finally, we found that the ability of these GAX deletions to induce G(0)/G(1) arrest correlates with their ability to transactivate the p21(WAF1/CIP1) promoter. We conclude that GAX activates p21(WAF1/CIP1) through multiple upstream AT-rich sequences. Given the multiple biological activities of GAX in regulating EC function, identification of a putative GAX-binding site will allow the study of how GAX activates or represses other downstream targets to inhibit angiogenesis.
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