Abstract:
:Vitamin A is metabolized to several biologically active compounds, the best known of which is retinoic acid. This compound has been shown to inhibit the growth of a variety of tumor cells and to induce a more differentiated phenotype in several tumor types. Vitamin D is metabolized to the active compound 1,25-dihydroxyvitamin D3. This vitamin is well-known for its role in maintaining calcium homeostasis in the body. Recently it has been shown that vitamin D3 can also inhibit tumor cell replication and stimulate differentiation of selected tumor types. Retinoic acid is being used clinically to treat promyelocytic leukemia, head and neck tumors as well as cervical dysplasia. Use of vitamin D3 clinically has been restricted by its affect on calcium metabolism. Recently, however, new analogs of vitamin D3 have been developed which have much less calcium mobilizing activity, yet still retain their tumor inhibitory properties. The action of both of these vitamins is mediated by nuclear receptors which have the same structure as steroid receptors. There are three nuclear retinoic acid receptors (RAR alpha, beta, and gamma), but only one vitamin D3 nuclear receptor. These receptors are expressed in very small amounts. Since the ligand should be in vast excess of receptor (ie not limiting), we explored the possibility that response to vitamin A might be mediated by control of RAR expression. Using B16 mouse melanoma cells as a model system, we found that RAR alpha and gamma mRNAs were constitutively expressed. RAR beta mRNA was induced by treatment of the cells with RA. Induction of RAR beta mRNA occurred within 1h and was not inhibited by cycloheximide. The mRNA for all three RARs was dramatically decreased with 8-bromo-cyclic AMP treatment and could not be rescued by addition of RA. Analysis of RAR gamma revealed that this decrease occurred within 1h of exposure to 8-bromo-cyclic AMP and was not blocked by simultaneous treatment with cycloheximide. Nuclear extracts from cyclic AMP-treated cells showed a large decrease in protein binding to a retinoic acid response element (RARE) oligonucleotide compared to control cells. This correlated with a marked reduction of RA-stimulated RARE-reporter gene activity in transfected cells which were treated with cyclic AMP. Pre-treatment of B16 cells with cyclic AMP prior to RA addition dramatically reduced induction of PKC alpha, an early marker of RA-induced cell differentiation. Thus, cyclic AMP can antagonize the physiological actions of RA via its ability to inhibit RAR expression.
journal_name
Adv Exp Med Bioljournal_title
Advances in experimental medicine and biologyauthors
Niles RMdoi
10.1007/978-1-4899-0949-7_1subject
Has Abstractpub_date
1995-01-01 00:00:00pages
1-15eissn
0065-2598issn
2214-8019journal_volume
375pub_type
杂志文章abstract::Herbert Hultgren, a cardiologist who kept a careful diary all his career, arrived in Peru at the beginning of 1959 to study the occurrence of pulmonary hypertension in children at high altitude with patent ductus arteriosus. There, he was told about a strange condition, high altitude pulmonary edema (HAPE), and found ...
journal_title:Advances in experimental medicine and biology
pub_type: 传,历史文章,杂志文章
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journal_title:Advances in experimental medicine and biology
pub_type: 杂志文章
doi:10.1007/978-1-4615-3448-8_14
更新日期:1992-01-01 00:00:00
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pub_type: 杂志文章,评审
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journal_title:Advances in experimental medicine and biology
pub_type: 杂志文章
doi:10.1007/978-1-4615-4863-8_61
更新日期:1998-01-01 00:00:00
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journal_title:Advances in experimental medicine and biology
pub_type: 杂志文章
doi:10.1007/978-1-4684-5643-1_52
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pub_type: 杂志文章
doi:10.1007/978-3-319-93791-5_5
更新日期:2018-01-01 00:00:00
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journal_title:Advances in experimental medicine and biology
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journal_title:Advances in experimental medicine and biology
pub_type: 杂志文章
doi:10.1007/978-1-4615-4857-7_25
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journal_title:Advances in experimental medicine and biology
pub_type: 杂志文章
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journal_title:Advances in experimental medicine and biology
pub_type: 杂志文章
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journal_title:Advances in experimental medicine and biology
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pub_type: 杂志文章,评审
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journal_title:Advances in experimental medicine and biology
pub_type: 杂志文章,评审
doi:10.1007/978-1-4899-2626-5_3
更新日期:1991-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1007/978-0-387-74911-2_3
更新日期:2008-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:1984-01-01 00:00:00
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journal_title:Advances in experimental medicine and biology
pub_type: 杂志文章,评审
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更新日期:2017-01-01 00:00:00
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