Sustaining proliferative signaling
Suppression of PTEN transcription by UVA.
Although ultraviolet A (UVA; 315-400 nm) has different physical and biological targets than ultraviolet B (UVB; 280-315 nm), the contribution of UVA to skin cancer susceptibility and its molecular basis remain largely unknown. Here we show that chronic UVA radiation suppresses phosphatase and tensin homolog (PTEN) expression at the mRNA level. Subchronic and acute UVA radiation also downregulated PTEN in normal human epidermal keratinocytes, skin culture, and mouse skin. At the molecular level, chronic UVA radiation decreased the transcriptional activity of the PTEN promoter in a methylation-independent manner, whereas it had no effect on the protein stability or mRNA stability of PTEN. In contrast, we found that UVA-induced activation of the Ras/ERK/AKT and NF-kB pathways plays an important role in UV-induced PTEN downregulation. Inhibiting extracellular signal-regulated kinases (ERK) or protein pinase B (AKT) increases PTEN expression. Our findings may provide unique insights into PTEN downregulation as a critical component of UVA's molecular impact during keratinocyte transformation.