Vitamin A or retinol primarily from the diet plays a critical role in normal neural crest development. The metabolism and storage of retinol is mediated by a number of binding proteins and enzymes. Intracellu-lar retinol is metabolized to all-trans retinoic acid (ATRA). All-trans retinoic acid is a major mediator of the effects of vitamin A via activation of a number of RAR and RXR nuclear receptors that heterodimerize and regulate gene transcription (see below). Exposure of human neuroblastoma cell lines to supra-physiologic doses (micromolar) of ATRA caused a reduction of cell growth and induction of neurite extension and differentiation that was ultrastructurally, biochemically, and electro-physiologically similar to normal neural cells (Fig. 15.2; Sidell 1982; Abemayor and Sidell 1989).

The ATRA treatment of NB cells was accompanied by a decrease in the expression (Thiele et al. 1985) and transcription (Thiele and Israel 1988) of the MYCN gene. The decrease in MYCN expression preceded the ATRA-induced G1 arrest and evidence of morphologic differentiation (Thiele et al. 1985), and the MYCN over-expression blocked differentiation (Peverali et al. 1996). All-trans retinoic acid induced decreases in MYCN levels and increases in the cy-clin-dependent kinase inhibitor p27 which may mediate the G1 arrest of NB cell cycle (Matsuo and Thiele 1998; M. Nakamura et al. 2003). Pulse therapy with retinoic acid showed a sustained arrest of tu

mor cell proliferation in NB cell lines, suggesting that high-dose pulse retinoid therapy (as opposed to the more traditional low-dose continuous retinoid therapy) might be effective in vivo (Reynolds et al. 1991).

Gaining Weight 101

Gaining Weight 101

Find out why long exhausting workouts may do more harm than good. Most of the body-building workout and diet regimens out there are designed for the guys that gain muscle and fat easily. They focus on eating less and working out more in order to cut the excess fat from their bodies while adding needed muscle tone.

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