Retinoids molecular mechanisms

Hepatocellular carcinoma (HCC) develops in patients with chronic liver diseases associated with hepatitis B and hepatitis C vims infections with high incidences. Here, an acyclic retinoid has been shown to suppress the posttherapeutic recurrence after interferon-y or glycerrhicin treatment in cirrhotic patients who underwent curative treatment of preceding tumors. The retinoid induced the disappearance of serum lectin-reactive a-fetoprotein (AFP-L3), a tumor marker indicating the presence of unrecognizable tumors in the remnant liver, suggesting a deletion of such minute (pre)malignant clones (clonal deletion). As a molecular mechanism of the clonal deletion, a novel mechanism of... 

Although results obtained in this test system are of major importance for understanding of cellular and molecular mechanisms (these are discussed at length in Chapter 12), this is not a practical routine assay for evaluating large numbers of retinoids. Personnel highly experienced in cell culture are required for proper maintenance of the cell line, and the assay takes 5-6 weeks to complete. 

The effects of retinoids on differentiation of epithelia in organ culture undoubtedly result from a combination of complex cellular responses and interactions of different cell types in the explant. These systems therefore have definite limitations for analysis of the molecular mechanism of action of the retinoids. The introduction of cell culture methodology to such studies was therefore of great importance and now is allowing molecular investigation of the role of retinoids in proliferation and differentiation. 

The single theme that continually recurs in all studies of the cellular mechanism of action of retinoids is that they modify cell differentiation and cell proliferation. However extensive the data that we have just summarized on the effects of retinoids on individual cellular enzymes, effectors, structural proteins, or glycoconjugates, they fail to provide a satisfactory explanation of the molecular mechanism of action of retinoids because they fail to consider the central role of the genes of the cell in control of differentiation and proliferation. Ultimately, it would appear that the problem of the molecular mechanism of action of... 

The importance of retinoids in the field of cancer studies has been discussed at length in these two volumes, particularly in Chapters 5 and 12. The ability of retinoids to modify the differentiation and proliferation of both preneoplastic and neoplastic cells is one of the fundamental properties of this class of substances and has been successfully used as the basis for several biological assays for retinoids, as documented in detail in Chapter 5. The use of preneoplastic and neoplastic cells to study the cellular and molecular mechanism of action of... 

Zelent A (1995) Molecular mechanisms of retinoid action. In L Degos, DR Parkinson (eds) Retinoids in Oncology. Springer-Verlag, Heidelberg, 3-25... 

Pharmacology and molecular mechanisms of retinoid action in skin... 

Activator protein-1 (AP-1) is an important transcription factor that figures in the inflammation response. AP-1 is a dimeric complex of the protooncoproteins jun and fos that is induced by growth factors, cytokines, tumor promoters, and sunlight [39]. Activation of AP-1 increases the transcription of cytokines, such as interleukin-2, and certain matrix metalloproteinases [40]. In the presence of t-RA, RARs can inhibit the actions of AP-1. Reciprocally, elevated expression of either the jun or fos components of AP-1 can prevent activation of RAREs by RARs. This repression of gene transcription, called transrepression, is a well-known mechanism for crosstalk between retinoid receptors and AP-1 [41-43]. The molecular mechanism of transrepression described for in vitro systems is dependent on the presence of t-RA and is believed to involve direct or indirect protein-protein interactions between retinoid receptors and AP-1 components (jun and fos), and/or competition between retinoid receptors and AP-1 for a common factor (or factors) required for their activities [42, 43]. However, this phenomenon studied in the context of photoaging of human skin in vivo has revealed a novel mechanism. 

This chapter reviews the cellular mechanism of action of retinoids, which is the central unsolved problem in retinoid biology and biochemistry. The problem of the role of retinoids in maintaining the normal physiology of the body as a whole, and of its various constituent oigans, has been essentially solved. However, at the cellular and molecular levels of investigation, it is not yet possible to present a consistent, unifying analysis of the mechanism of action of retinoids which provides a comprehensive explanation of the experimental data. 

Recent cellular and molecular studies have pointed to numerous mechanisms by which VA and related retinoids can potentially regulate the immune system. Evidence exists for retinoid-modulation of antigenic activation of T lymphocytes, activation of monocytes, and B cell differentiation. Retinoids are likely to be involved in a direct manner in regulating the production of... 

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