Ultraviolet B-Radiation Dose Influences the Induction of Apoptosis and p53 in Human Keratinocytes

Cotton, Jenny; Spandau, Dan F.

doi:10.2307/3579415

Cited by 85 publications

(69 citation statements)

References 19 publications

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“…The cellular response to UV radiation involves the activation of many genes, including p53. The increased expression of p53 protein is cell-type speci®c and has been demonstrated in keratinocytes (Cotton and Spandau, 1997). Once expression is activated, p53 can regulate genes involved in both cell cycle arrest and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

et al. 1999

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The epidermis is continually exposed to harmful mutagens that have the potential to cause DNA damage. To protect the skin from accumulating mutated cells, keratinocytes have developed a highly regulated mechanism of eliminating damaged cells through apoptosis. Bclx L is a well-described cell survival protein that when overexpressed in skin can protect keratinocytes from UV radiation-induced apoptosis. To begin to unravel the complex mechanisms that keratinocytes use to survive, we wanted to characterize the role of endogenous Bcl-x L in protecting cells from death. In this study, we describe the development and characterization of an antisense inhibitor to Bcl-x L . We show that this inhibitor reduces Bcl-x L RNA and protein in a concentration-dependent, sequence-speci®c manner. Furthermore, treatment of keratinocytes and epithelial cells with this inhibitor sensitizes these cells to UV-B radiation and cisplatinum treatment-induced apoptosis. Thus, these results o er direct evidence that Bcl-x L is critical in the protection of skin and epithelial cells from apoptosis and provide a basis for the role of Bcl-x L in keratinocyte and epithelial cell survival.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

et al. 1999

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“…Interestingly, p53 simultaneously induces cascade of events for G 1 arrest and apoptosis in same cell type (28); for example high doses of UV irradiation induce apoptosis in human keratinocytes, and low doses activate repair of UV-induced DNA damage (29). Ability of p53 to promote growth arrest/repair and thus survival on one hand, but apoptosis on other, raises the question of what determines the choice between these two opposite events?…”

Section: Discussionmentioning

confidence: 99%

Silibinin Protects against Photocarcinogenesis via Modulation of Cell Cycle Regulators, Mitogen-Activated Protein Kinases, and Akt Signaling

et al. 2004

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Here, we assessed the protective effect of silibinin on UVB-induced skin carcinogenesis in SKH-1 hairless mice. Topical application of silibinin before or immediately after UVB exposure or its dietary feeding resulted in a strong protection against photocarcinogenesis, in terms of tumor multiplicity (60 -66%; P < 0.001), tumor volume per mouse (93-97%; P < 0.001) and tumor volume per tumor (80 -91%; P < 0.001). Silibinin also moderately inhibited tumor incidence (5-15%; P < 0.01) and delayed tumor latency period (up to 4 weeks; P < 0.01-0.001). To investigate in vivo molecular mechanisms of silibinin efficacy, tumors and uninvolved skin from tumor-bearing mice were examined immunohistochemically for proliferation, p53, apoptosis, and activated caspase-3. Silibinin treatment showed a strong decrease (P < 0.001) in proliferating cell nuclear antigenpositive cells and an increase in p53-positive (P < 0.005-0.001), terminal deoxynucleotidyltransferase-mediated nick end labeling-positive (P < 0.005-0.001), and cleaved caspase-3-positive cells (P < 0.001). Western blot analysis of normal skin and tumor lysates showed that silibinin decreases the levels of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 and associated cyclins A, E, and D1, together with an up-regulation of Cip1/p21, Kip1/p27, and p53. Silibinin also showed a strong phosphorylation of extracellular signal-regulated protein kinase 1/2, stress-activated protein kinase/c-JUN NH 2 -terminal kinase 1/2, and p38 mitogen-activated protein kinases but inhibited Akt phosphorylation and decreased survivin levels with an increase in cleaved caspase-3. Together, these results show a strong preventive efficacy of silibinin against photocarcinogenesis, which involves the inhibition of DNA synthesis, cell proliferation, and cell cycle progression and an induction of apoptosis. Furthermore, these results also identify in vivo molecular mechanisms of silibinin efficacy against photocarcinogenesis.

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“…This has been mimicked by the EHS used in this study where any photodamaged cell would remain localized within the epidermis and subject to regulation via interactions with surrounding cells. The low doses of UV used in this study are also an important consideration because they should be too low to induce apoptosis 34,35 or possibly even cell cycle arrest. However, these low doses of UV induced an increase of p53 immunoreactive cells especially at the base of the epidermis, which may indicate damage to p53.…”

Section: Discussionmentioning

confidence: 99%

Ultraviolet A within Sunlight Induces Mutations in the Epidermal Basal Layer of Engineered Human Skin

Huang

Bernerd

Halliday

2009

The American Journal of Pathology

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The ultraviolet B (UVB) waveband within sunlight is an important carcinogen; however, UVA is also likely to be involved. By ascribing mutations to being either UVB or UVA induced, we have previously shown that human skin cancers contain similar numbers of UVBand UVA-induced mutations, and, importantly, the UVA mutations were at the base of the epidermis of the tumors. To determine whether these mutations occurred in response to UV, we exposed engineered human skin (EHS) to UVA, UVB, or a mixture that resembled sunlight, and then detected mutations by both denaturing high-performance liquid chromatography and DNA sequencing. EHS resembles human skin, modeling differential waveband penetration to the basal, dividing keratinocytes. We administered only four low doses of UV exposure. Both UVA and UVB induced p53 mutations in irradiated EHS, suggesting that sunlight doses that are achievable during normal daily activities are mutagenic. UVA-but not UVB-induced mutations predominated in the basal epidermis that contains dividing keratinocytes and are thought to give rise to skin tumors. These studies indicate that both UVA and UVB at physiological doses are mutagenic to keratinocytes in EHS. (Am J Pathol

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Ultraviolet B-Radiation Dose Influences the Induction of Apoptosis and p53 in Human Keratinocytes

Cited by 85 publications

References 19 publications

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

Silibinin Protects against Photocarcinogenesis via Modulation of Cell Cycle Regulators, Mitogen-Activated Protein Kinases, and Akt Signaling

Ultraviolet A within Sunlight Induces Mutations in the Epidermal Basal Layer of Engineered Human Skin

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