Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously that p53(-/-) fibroblasts show greater sensitization by caffeine to the lethal effects of ionizing radiation compared with p53(+/+) cells. Recently published data have suggested a possible role of p53 in nucleotide excision repair: an association of p53 and xeroderma pigmentosum group B protein and a greater sensitivity to cisplatin of RKO cells transfected with the E6 protein of human papilloma virus (inactivating p53). We show that p53(+/+) and p53(-/-) cells have equal sensitivity to germicidal UV light (as with ionizing radiation). However, the introduction of 2 mM caffeine led to a sensitization enhancement ratio (at 10% survival) of 1.8 in p53(-/-) cells, but only 1.3 in wild-type (p53+/+) cells. Lower doses of caffeine had less effect, and 0.1 mM caffeine resulted in no detectable sensitization of either cell type to UV light in contrast to X-rays. The differential sensitivity of p53(-/-) cells to X-rays and caffeine was thought to be due to override of the G2-M block to cell cycle progression. In response to UV light, cells accumulate in S phase, and the magnitude of S-phase accumulation was observed to be greater in p53(-/-) cells. Caffeine had little effect on the cell cycle distribution in p53(+/+) cells. However, for p53(-/-) cells, a greater proportion were in S phase after treatment with caffeine, and a complete loss of S-phase delay was observed after UV irradiation. In conclusion, the role of p53 in nucleotide excision repair appears to be of little significance for cell survival. Greater sensitization of p53(-/-) cells to caffeine could be mediated via override of S-phase delay.
 ...
PMID:p53-null cells are more sensitive to ultraviolet light only in the presence of caffeine. 939 72

The p53 tumour suppressor is a transcription factor that can either activate or repress the expression of specific genes in response to cellular stresses such as exposure to ultraviolet light. The p53 protein can exert both pro- and anti-apoptotic effects depending on cellular context. In primary human fibroblasts, p53 protects cells from UV-induced apoptosis at moderate doses but this is greatly affected by the nucleotide excision repair (NER) capacity of the cells. The damage-specific DNA binding protein 2 (DDB2) is involved in NER and is associated with xeroderma pigmentosum subgroup E (XP-E). Importantly, DDB2 is also positively regulated by the p53 protein. To study the potential interplay between DDB2 and p53 in determining the apoptotic response of primary fibroblasts exposed to UV light, the expression of these proteins was manipulated in primary normal and XP-E fibroblast strains using human papillomavirus E6 protein (HPV-E6), RNA interference and recombinant adenoviruses expressing either p53 or DDB2. Normal and XP-E fibroblast strains were equally sensitive to UV-induced apoptosis over a broad range of doses and disruption of p53 in these strains using HPV-E6 or RNA interference led to a similar increase in apoptosis following exposure to UV light. In contrast, forced expression of p53 or DDB2 did not affect UV-induced apoptosis greatly in these normal or XP-E fibroblast strains. Collectively, these results indicate that p53 is primarily protective against UV-induced apoptosis in primary human fibroblasts and this activity of p53 does not require DDB2.
 ...
PMID:The anti-apoptotic role for p53 following exposure to ultraviolet light does not involve DDB2. 1942 72