Nuclear mechanism

Advances have been made in the localization of the cellular sites of l,25-(OH)2D3 in target tissue. Receptor proteins have been extracted, and, in the case of the chick intestinal receptor, purified to homogeneity.451 The ability of l,25-(OH)2D3 to stimulate absorption of calcium is blocked reversibly by inhibitors of RNA and protein synthesis. This suggests that l,25-(OH)2D3 functions by a nuclear mechanism. 

Laimnerding, J., Schulze, P, Takahashi, T, Kozlov, S., Sullivan, T, Kamm, R., Stewart, C. and Lee, R. (2004) Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J. Clin. Invest. 113, 370-378. 

As mentioned earlier, there are two electron-nuclear mechanisms that result in relaxation of the carbon nucleus dipolar and scalar. A dipolar mechanism can be thought of as a through-space effect, whereas a scalar mechanism is a through-bond effect. Therefore, it might be envisaged that the scalar mechanism is limited, because the transmission of electron density is rather restricted through sigma bonds. However, it does occur, and quantitative distance information is difficult to obtain from this mechanism. 

Horwitz, K.B. and McGuire, W.L. (1978) Nuclear mechanisms of estrogen action. Effects of estradiol and anti-estrogens on estrogen receptors and nuclear receptor processing. The Journal of Biological Chemistry, 253, 8185-8191. 

Later researches, chiefly by J. J. Thomson, Rutherford, Aston, and Dempster, have shown that the nucleus itself is further built up of electrons and hydrogen nuclei, called protons. As a consequence of these investigations the old hypothesis of Prout regains significance, in a somewhat different form. The deviations of the atomic weights from whole-number values, which previously ruled out this hypothesis, can be accounted for by the conception of isotopes and energy-mass variations. Not much is definitely known on the subject of nuclear mechanics, and it will not be discussed in this book. 

Interestingly, the amino-terminal extensions contain putative nuclear localization sequences that appear to be involved in transport of these proteins into the nucleus (Acland et al., 1990 Amalric et al., 1991 Bugler et al., 1991 Kiefer et al., 1994). FGF-1 has also been shown to enter the nucleus, but the amino acid sequence involved in this process remains to be elucidated (Cao et al., 1993). The specific function of nuclear FGF is still unclear, but there is evidence that FGF-2 import into the nucleus is involved in the mitogenic response of endothelial cells to FGF (Bouche et al., 1987 Baldin et al., 1990). Such a nuclear mechanism of FGF action could supplement the classical signal pathway by receptor-mediated mechanisms. 

The next stage involves the synthesis of specific calcium-binding proteins, typified by the intestinal CaBP discussed in Section 62.1.3.4.5, which probably stimulates the transport of calcium. The role of the protein in vitamin D-dependent absorption of calcium is supported by the good correlation between the concentration of CaBP and the rate of calcium absorption. Under conditions of low calcium or phosphorus diets, chicks and other animals produce more intestinal CaBP to increase the efficiency of uptake of calcium. In general, adaptation to a low calcium diet involves increased synthesis of l,25-(OH)2D3 and the intestinal CaBP. Lowered requirements for calcium in old age are manifested by lower levels of both factors. Advances have been made in the localization of the cellular sites of l,25-(OH)2D3 in target tissue. Receptor proteins have been extracted, and, in the case of the chick intestinal receptor, purified to homogeneity." The ability of l,25-(OH)2D3 to stimulate absorption of calcium is blocked reversibly by inhibitors of RNA and protein synthesis. This suggests that l,25-(OH)2D3 functions by a nuclear mechanism. 

Lammerding, J., P.C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R.D. Kamm, G.L. Stewart, and R.T. Lee. 2004. Lamin a/c deficiency causes defective nuclear mechanics and mechanotransduction. Journal of Clinical Investigation 113(3) 370-8. 

Pin, S. Chen, H. Lein, P. J. Wang, M. M. Nucleic acid binding agents exert local toxic effects on neurites via a non-nuclear mechanism. J. Neurochem. 2006, 96, 1253-1266. 

Although it is generally agreed that steroid and thyroid hormones act in the nucleus of the target cell to induce specific protein synthesis, there are data which suggest that thyroid hormone (Sterling, 1979) and 1,25-dihydroxycholecalciferol (Bikle et al., 1979) may also act via extra-nuclear mechanisms. 

---