Nuclear localization

On pharmacodynamic grounds, tumor resistance may be caused by such diverse mechanisms as the mutation or redundancy of topo II, the overexpression and preferred nuclear localization of proteasome a-type subunits (leading to a anomalous degradation of topo II), genetic deletion or loss-of-function mutations of p53, overexpression of ROS-detoxifying enzymes, overexpression of Bcl-2 (leading to a diminished cyt c release), etc. However, none of these factors would universally predict the development of anthracycline-resistance in a given tumor or another. 

Importins are transport proteins at the nuclear pore complex, needed for the selective import of proteins into the nucleus. They recognize nuclear localization signal sequences of cargo proteins. 

The NHR contains also the conserved Calcineurin docking site, PxlxIT, required for the physical interaction of NEAT and Calcineurin. Dephosphorylation of at least 13 serines residues in the NHR induces a conformational change that exposes the nuclear localization sequences (NLS), allowing the nuclear translocation of NEAT. Rephosphorylation of these residues unmasks the nuclear export sequences that direct transport back to the cytoplasm. Engagement of receptors such as the antigen receptors in T and B cells is coupled to phospholipase C activation and subsequent production of inositol triphosphate. Increased levels of inositol triphosphate lead to the initial release of intracellular stores of calcium. This early increase of calcium induces opening of the plasma membrane calcium-released-activated-calcium (CRAC) channels,... 

Sequence of amino acids that determine the transport of proteins into the nucleus. Although there is no clear consensus, nuclear localization signals tend to be rich in positively charged residues, which allow interaction with proteins from the nuclear import machinery (i.e., importins). 

Sarge, K.D., Murphy, S.P., Morimoto, R.l. (1993). Activation of heat shock gene transcription by heat shock factor 1 involves oligomenzation, acquisition of DNA binding activity, and nuclear localization and can occur in the absence of stress. Mol. Cell. Biol. 13. 1392-1407. 

Best, T. B., B.S. Edelson, N.G. Nickols, and P. B. Dervan. Nuclear localization of pyrrole-imidazole polyamide-fluorescein conjugates in cell culture. Proc. Natl. Acad. Sci. USA 2003, 100, 12063-12068. 

Boffa L.C., Scarf S., Marian M.R., Dai40nte G, Allfrey V.G., Benatti U., Morris O. L. Dihydrotestosterone as a selective cellular/nuclear localization vector for anti-gene peptide nucleic acid in prostatic carcinoma cells. Cancer Res. 2000 60 2258-2262. 

CuTRONA G., Carpaneto E.M., Ulivi M., Roncella S., Landt O., Ferrarini M., Boeea L. C. Effects in live cells of a c-myc anti-gene PNA linked to a nuclear localization signal. Nature Biotechnol. 

Figure 43-10. Regulation of the NF-kB pathway. NF-kB consists of two subunits, p50 and p65, which regulate transcription of many genes when in the nucleus. NF-kB Is restricted from entering the nucleus by IkB, an Inhibitor of NF-kB. IkB binds to—and masks—the nuclear localization signal of NF-kB.

NLS, nuclear localization signal PTS, peroxisomal-matrix targeting sequence. 

NI, nuclear inclusions (c), normal cytoplasmic localization (n), normal nuclear localization (membr), normal membrane localization. 

Perez MK, Paulson HL, Pendse SJ, Saionz SJ, Bonini NM, Pittman RN. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 1998 143 1457-1470. 

Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HT. Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice [see comments]. Cell 1998 95 41-53. 

Booher, R., and Beach, D. (1986). Site-specific mutagenesis of cdc2+, a cell cycle control gene of the fission yeast Schizosaccaromyces pombe. Mol. Cell. Biol. 6 3523-3530. Booher, R. N., Alfa, C. E., Hyams, J. S., and Beach, D. H. (1989). The fission yeast cdc2/cdcl3/sucl protein kinase regulation of catalytic activity and nuclear localization. CeU 58 485-497. 

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