Retinoic acid (RA), the major biologically active form of vitamin A, plays important roles in regulating a broad range of biological processes. / Progressive loss of RARs is associated with skin carcinogenesis both in human and animals. Despite such observations, the biological significance of RAR loss in skin carcinogenesis has not yet been clarified. To this end, we established keratinocyte cell lines deficient in RARalpha, RARgamma, or both and employed a well-established tumorigenesis model to investigate whether loss of RARs is causally related to skin tumorigenesis. We found that RARgamma is the major RAR subtype mediating the growth and AP-1 inhibitory effects of RA on keratinocytes in vitro. Consistent with this observation, loss of RARgamma, but not RARalpha, predisposed keratinocytes to tumor formation, suggesting that RARgamma may act as a tumor suppressor. Reconstitution of RARs in the RARalphagamma-/- keratinocytes inhibited their tumorigenic potential, further proving that RARs have tumor suppressive effects. / As expected, expression of dnRARalpha resulted in profound epidermal defects. Intriguingly, dnRAalphaDBD caused a virtually identical skin phenotype, suggesting that dnRARalpha acts to affect epidermal development via a DNA-binding-independent mechanism. The epidermal phenotype of these transgenic mice is reminiscent of that seen in the p63-/- mice, and p63 expression was indeed significantly reduced in the epidermis expressing dnRARalpha or dnRARalphaDBD, suggesting that downregulation of p63 by dnRARalpha may be attributable to the epidermal phenotypes associated with the transgenic mice. These observations also suggest that DNA-binding is not required for dnRARalpha to attenuate p63 expression in the epidermis. Consistent with these observations, I also found that p63 is indeed not a RAR-target, as no overt changes in p63 expression were observed in the RARalphagamma-/- epidermis, which appeared normal. (Abstract shortened by UMI.)
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84492 |
| Date | January 2003 |
| Creators | Chen, Changfeng |
| Contributors | Lohnes, David (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002141084, proquestno: AAINQ98225, Theses scanned by UMI/ProQuest. |
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