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Fig. 1. Transcriptional regulation of PTEN. Illustrated are the pathways recently found to be involved in the regulation of PTEN transcription. Components of activating pathways are displayed as ovals and those of suppressing pathways as rectangles (note that some function as both activators and repressors). JUN was found to suppress PTEN transcription by binding to a variant activator 1 (AP-1) site, called PF1, roughly 19 kb upstream of the transcriptional start site (Hettinger et al., 2007). Activation of PPAR by its selective ligands of the glitazone (Glit) group, used in the treatment of diabetes, upregulates PTEN expression by binding to two PPAR response elements (PPREs) (Patel et al., 2001). Upregulation of PTEN by glitazones has been observed by several other groups (Han and Roman, 2006; Lee et al., 2005; Zhang, W. et al., 2006). Phytoestrogens, such as genistein from soybeans, indole-3-carbinole from cruciferous vegetables like broccoli, and resveratrol found in red wine, lead to an increase in PTEN mRNA (Waite et al., 2005) and protein (Dave et al., 2005; Waite et al., 2005). In pancreatic cancer cells, TGF positively regulates PTEN transcription in a SMAD-dependent manner and negatively controls it in a SMAD-independent way (Chow et al., 2007). Furthermore, in a mesangial cell model for diabetic nephropathy, in which high glucose levels lead to a decrease in PTEN (protein) expression, this decrease was found to be mediated by suppressive effects of TGF (Mahimainathan et al., 2006). By contrast, binding of growth factor (GF) to its receptors in the cell membrane activates, via RAS, human SPRY2 (hSPRY2) to upregulate PTEN transcription (Edwin et al., 2006). Resistin, a peptide secreted by adipocytes and other cell types during inflammation, also positively regulates PTEN transcription. Resistin leads to activation of the p38 pathway and of ATF2, as well as to the binding of ATF2 to the PTEN promoter (shown in orange) to two ATF binding sites (Shen et al., 2006). Moreover, MKK4 inhibits PTEN transcription by activating NFB, a transcriptional repressor that binds to the PTEN promoter 1.5 kb upstream of the ATG (Xia et al., 2007). p53 regulates PTEN both positively at the transcriptional level and negatively at the protein-stability level: a functional p53 response element (RE) has been found in the PTEN promoter, and p53 induction leads to elevated PTEN mRNA and protein levels (Stambolic et al., 2001; Tang and Eng, 2006b). PTEN might autoregulate its own expression through stabilization of p53 protein independently of its phosphatase activity (Tang and Eng, 2006b). EGR1 binds to the PTEN promoter and upregulates its expression in response to radiation (Virolle et al., 2001) and IGF2 (Moorehead et al., 2003). (For pathways marked with a star, no specific PTEN promoter site has been identified as being involved in the regulation observed.) Solid lines represent demonstrated direct interaction of the respective protein with DNA; broken lines indicate indirect action.

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