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| Differentiation-dependent p53 regulation of nucleotide excision repair in keratinocytes |
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| Author(s): Li G, Ho VC, Mitchell DL, Trotter MJ, Tron VA |
| Source: AMERICAN JOURNAL OF PATHOLOGY Volume: 150 Issue: 4 Pages: 1457-1464 Published: APR 1997 |
| Times Cited: 55 References: 53 |
| Abstract: The role of the tumor suppressor p53 in repair of ultraviolet light (UV)-induced DNA damage was evaluated using a host-cell reactivation (HCR) assay. HCR determines a cell's ability to repair W-damaged DNA through reactivation of a transfected CAT reporter plasmid. Most UV damage is removed through nucleotide excision repair (NER). Primary murine keratinocytes isolated from p53-deficient and wild-type p53 mice were used in the HCR assay The NER was reduced in p53(-/-) keratinocytes as compared with p53(-/-) keratinocytes. The reduced DNA repair in p53(-/-) mice was confirmed with a radioimmunoassay comparing cyclobutane dimers (CPDs) and (6-4) photoproducts in P53(+/+) and p53(-/-) keratinocytes after the cells were exposed to UV irradiation. Our results demonstrate that wildtype p53 play's a significant role in regulating NER. Furthermore, as there is evidence that p53 protein levels decrease after keratinocytes become differentiated, we sought to determine whether p53 plays a role in NER in differentiated keratinocytes. Differentiation of the keratinocytes by increasing the Ca2+ concentration in the culture media resulted in a marked reduction in NER equally in both p53(+/+) and p53(-/-) groups. This finding suggests that reduced DNA repair after differentiation is p53 independent. A similar reduction in HCR was confirmed in differentiated human keratinocytes. These data, taken together, indicate that P53 or p53-regulated proteins enhance NER in basal undifferentiated keratinocytes but not in differentiated cells. As non-melanoma skin cancers originate from the basal keratinocytes, our findings suggest that loss of p53 may contribute to the pathogenesis of this common skin cancer. |
| Document Type: Article |
| Language: English |
Addresses:
1. VANCOUVER HOSP & HLTH SCI CTR, DEPT PATHOL, VANCOUVER, BC V5Z 1L8 CANADA
2. VANCOUVER HOSP & HLTH SCI CTR, DEPT MED, DIV DERMATOL, VANCOUVER, BC V5Z 1L8 CANADA
3. UNIV BRITISH COLUMBIA, BRITISH COLUMBIA CANC AGCY, VANCOUVER, BC V5Z 1M9 CANADA
4. UNIV TEXAS, MD ANDERSON CANC CTR, DEPT CARCINOGENESIS, SMITHVILLE, TX 78957 USA |
| Publisher: AMER SOC INVESTIGATIVE PATHOLOGY, INC, 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 |
| Subject Category: Pathology |
| IDS Number: WR012 |
| ISSN: 0002-9440 |
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