Regulation of Vascular Endothelial Growth Factor Expression in Human Keratinocytes by Retinoids

Abstract

Vascular endothelial growth factor (VEGF) is overexpressed in hyperproliferative diseases, such as psoriasis and cancers, which are characterized by increased angiogenesis. Experimentally, VEGF overexpression can be induced by the treatment of cell cultures and biological tissues with phorbol esters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA). Using normal human keratinocytes in conventional cultures and skin grafted onto nude mice in vivo, we show that retinoids can inhibit TPA-mediated VEGF gene induction at the transcriptional level. Because retinoids are biologically active either by interacting with the nuclear retinoic acid receptors or by interfering with the activator protein 1 (AP1) transcription factor, we studied the effect of the retinoic acid derivative CD 2409, which exhibits strong anti-AP1 activity but does not bind to the known retinoic acid receptors in vitro. The results demonstrate that the inhibition of VEGF expression by retinoids only depends on their anti-AP1 activity and does not require gene transactivation via retinoic acid response elements. Because the VEGF promoter contains four potential AP1 binding sites, we used different promoter constructs to identify the functional site responsible for TPA induction and retinoid inhibition. This site turned out to be localized at position ؊621 of the 5 flanking region of the VEGF gene.

Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-κB and JNK/AP1 pathways

“…Since vFLIP activates the NF-kB and AP1 family of transcription factors, vFLIP may induce expression of many genes through transactivation of the respective response elements, which are present in the promoters of many cytokines (e.g. the vascular endothelial growth factor promoter) and growth factors (Diaz et al, 2000).…”

Early growth response gene-1 plays a pivotal role in down-regulation of a cohort of genes in uterine leiomyoma

“…EGR1 targets identified in this study include genes playing roles in biological responses including cell cycle (EGR1, ATF3, FOS, and PTP4A1), apoptosis (EGR1, ATF3, SERPINE1, and PDGFB), angiogenesis (EGR1, PDGFB, SERPINE1, VEGF, CYR61, and F3), differentiation of smooth muscle cells (RORA and CSRP2), degradation and formation of extracellular matrix (VEGF, SERPIINE1, CYR61, and F3), responses to hypoxia (PDGFB and RORA), and metabolism of retinoids (FOS, VEGF, PDGFB, SERPINE1, HMGA1, and F3; Diaz et al 2000, Wu et al 2004. EGR1 is thus likely to contribute to the leiomyoma phenotype through down-regulation of these target genes.…”

Regulation of keratin expression by retinoids

“…61 One of the two RARα agonists, Am580/CD336, has previously been shown to downregulate VEGF and NOS-2 with similar efficiency as a pan-RAR agonist. 62,63 However, the role of RARα agonists as potent modulators of gene transcription in keratinocytes is obviously not a general phenomenon, since Am580/CD336 was less effective than retinoic acid in increasing the expression of other retinoid-regulated genes in cultured keratinocytes. 64 …”