Regulation of Gene Expression

Vitamin A regulates growth and differentiation of many types of cells and tissues. It affects particularly the mucosa of the respiratory tract (A): if the active metabolite retinoic acid (RA) is missing, patchy lack of cilia (A1-A3) results. At the same time, mucus-secreting cells increase in numbers. This disturbed differentiation causes a reduction in the lungs' ability to expel particles, making them more susceptible to infections. Sustained vitamin A deficiency leads to metaplasia of the respiratory epithelium (B, C), a precancerous stage. This may explain the relationship between low vitamin A supply and lung cancer. Since compounds in cigarette smoke like benzopyrene deplete the lungs' vitamin A storage, the resulting localized vitamin A deficiency may enhance the development of lung cancer. RA apparently also controls the morphogenesis of several tissues during embryonic development. Vitamin A deficiency as well as use of RA (as acne medication) during early pregnancy results in typical malformations: open back (spina bifida), cleft lips or palate, and malformations of arms and legs.

The biological effects of the active forms of RA are based on their interactions with two subfamilies of nuclear retinoic acid receptors and retinoid X receptors (RAR and RXR with their respective subtypes). RAR bind all-trans-retinoic acid with high affinity, altering gene expression through direct interaction with the ligand (D). RXR, even though they are also activated by all-trans-retinoic acid, have low affinity to this ligand. Other retinoids like 9-cis-retinoic acid bind much better here. Hence, isomerization of the all-trans- to the 9-cis form favors RXR-mediated effects of RA. To date, more than 30 different nuclear receptors for retinoids have been identified. The actual RAR/RXR effect on gene expression requires the binding of RXR (including its ligand-cis-RA) to another receptor (heterodimerization) (E). This receptor can be an RA, thyroid, vitamin D, estrogen, androgen, or progesterone receptor. Different types of heterodimerization can result in different forms of binding to DNA resulting in different gene expression. The retin-oid receptor works as a transcription factor, increasing transcription in proportion to the amount of RA present. RA has an inhibitory effect on other transcription factors like AP-1 (activation protein 1), which enhances gene expression of various proteins. It is thought that this occurs through heterodimerization of RAR and/or RXR with the subunits of AP-1, fos, and jun, which are proto-oncogenes. Since receptors for growth hormone, onco-genes, interleukins, cytokine, and cell-cell interaction factors like laminine and fibronectin interact with retinoid receptors, RA is an important regulator of growth as well as cell and tissue differentiation.

- A. Epithelial Changes Due to Vitamin A Deficiency -

Pseudo-stratified, columnar

Increase in secretory cells

Loss of ciliated cells

Increasing epithelial metaplasia

Epithelial metaplasia, stratified squamous

B. Healthy Respiratory Epithelium

- C. Marginal Vitamin A Deficiency-

i- D. The RAR Receptor

Binding to ligand

Binding to ligand

All-trans-retinoic acid

All-trans-retinoic acid

Binding to DNA

DNA-binding Ligand-

region binding region i- E. Heterodimerization -

Partner heterodimers

9-cis-Retinoic acid

9-cis-Retinoic acid

Ligand

RAR VDR

COOH TR

PPAR

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