p53-related apoptosis resistance and tumor suppression activity in UVB-induced premature senescent human skin fibroblasts

Abstract

Abstract. Chronic exposure to solar UV irradiation leads to photoaging, immunosuppression, and ultimately carcinogenesis. Cellular senescence is thought to play an important role in tumor suppression and apoptosis resistance. However, the relationships among stress-induced premature senescence (SIPS), tumorigenesis and apoptosis induced by UVB remain unknown. We developed a model of UVB-induced premature senescence in human skin fibroblasts (HSFs). After five repeated subcytotoxic UVB exposures at a dose of 10 mJ/cm 2 , the following biomarkers of senescence were markedly present: senescence-associated ß-galactosidase (SA ß-gal) activity, growth arrest, and the overexpression of senescenceassociated genes. Firstly, there was an increase in the proportion of cells positive for SA ß-gal activity. Secondly, there was a loss of replicative potential as assessed by MTT assay. FACS analysis showed that UVB-stressed HSFs were blocked mostly in the G1 phase of the cell cycle, and replicative senescence, and protein expression of p53, p21WAF-1 and p16INK-4a increased significantly. Thirdly, the mRNA levels of three senescence-associated genes, fibronectin, osteonectin and SM22, also increased. A real time PCR array to investigate the mRNA expression of p53-related genes involved in growth arrest, apoptosis and tumorigenesis indicated that p53, p21, p19, Hdm2, and Bax were up-regulated, and bcl, HIF-1α and VEGF were down-regulated. Collectively, our data suggest that UVB-induced SIPS plays an important role in p53-related apoptosis resistance and tumor suppression activity.

Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence

“…Instead, the mutation on p53 leading to the lack of apoptosis and the strong induction of cell cycle arrest and senescence may be the main contributor to hypersensitivity to UVB. Consistent with this, a recent study linked chronic UV exposure to premature senescence in human skin fibroblasts, 23 which may have direct impact on UV induced photoaging. Further research is required to investigate the role of p53-dependent apoptosis in UV-induced inflammation and immunosuppression.…”

“…19,20 Previous work revealed that in the absence of one or both alleles of p53, mice exhibit extreme sensitivity to tumor induction by UVB and a drastic decrease of apoptosis in the dermis. 21,22 More recent studies underline UVB as an inducer of p53-mediated premature cellular senescence 23,24 …”

Trans-Zeatin inhibits UVB-induced matrix metalloproteinase-1 expression via MAP kinase signaling in human skin fibroblasts

“…As previously described (15)(16)(17)(18)26), four F36T12 ERE-VHO UV tubes were used in this study as the UV source. A Kodacel TA401/407 filter was mounted 4 cm in front of the tubes to block UVC (wavelengths below 290 nm).…”

“…Furthermore, UV irradiation also activates growth factor receptors, which induce the activation of protein kinase cascades such as the MAP kinase (MAPK) signal transduction pathways in the cells (14)(15)(16)(17)(18). The MAPK signaling pathways regulate a variety of cellular functions, including the expression of MMPs and the inhibition of collagen production, which interferes with the metabolism of extracellular matrix (ECM) and causes the characteristic changes of photoaging in histo- (11,(19)(20)(21).…”

Single Exposure of Human Oral Mucosa Fibroblasts to Ultraviolet B Radiation Reduces Proliferation and Induces COX-2 Expression and Activation

“…In addition, differences in ECM production and matrix metalloproteinase (MMP) gene expression have been described between skin and oral mucosa fibroblasts, suggesting a different fibroblast phenotype depending upon the tissue of residence (11,12) . Studies analyzing the effects of UVB light on cultured skin fibroblasts showed that repeated exposure to subcytotoxic doses of UVB induces premature senescence (13) , resulting in a sharp decrease in cell proliferation (14) . In addition, UVB exposure of skin fibroblasts stimulates the expression of several cell cycle regulatory genes, such as p53, as well as, pro-inflammatory genes, such as COX-2 (14,15) .…”