Trends in Genetics
Research FocusThe ins and outs of transcriptional control: nucleocytoplasmic shuttling in development and disease
Section snippets
Of great import
Mutations in the sex determining region on the Y chromosome (SRY) account for ∼10% of all cases of XY sex reversal in humans 12, 13. The only functional domain of the SRY protein known to be conserved between species is the high-mobility group (HMG) domain, a 79-amino acid region involved in the specific binding and sharp bending of DNA 14, 15. The majority of SRY mutations resulting in XY sex reversal occur within the HMG domain, predominantly causing defects in binding to target DNA sequences
Nuclear family
In the dozen years since the discovery of SRY, a gene family has sprung up around it – the SOX or SRY-like HMG box genes [22]. These genes, as the name implies, encode proteins that contain an HMG domain related to that of SRY (usually with sequence identity at the amino acid level of >50% [23]. All of the well-characterized SOX genes, like their founding member SRY, are involved in embryonic development. SOX9 is involved in chondrocyte formation during skeletal development 24, 25 and is
In through the out door
Intuitively, a mechanism by which a transcription factor can be shunted into the nucleus would seem to be a basic requirement for its function once it is produced in the cell cytoplasm. It is perhaps not surprising that interference with this process could cause disruptions to proper cellular development. However, the story is not this simple. Recent data [10] suggest that active mechanisms for nuclear export and import are required for SOX9 function. Prior to sexual differentiation, SOX9
Conclusion
Active, continuous shuttling between nucleus and cytoplasm might prove to be important to the function of the majority of SOX proteins in development, and their malfunction in human disease. Certainly the importance of nuclear import and export of a range of SOX proteins can be tested experimentally using targeted mutation strategies in mice. In broader terms, the regulation of nucleocytoplasmic shuttling is clearly another level of control over how, when and where transcription factors operate
Acknowledgements
We thank Josephine Bowles, Megan Wilson and Annemiek Beverdam of the Koopman laboratory for critical reading of the manuscript. J.M.S. is the recipient of an Australian Postgraduate Award and a supplementary scholarship from the Institute for Molecular Bioscience. P.A.K. is a Professorial Research Fellow of the Australian Research Council.
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2010, International Journal of Biochemistry and Cell BiologyCitation Excerpt :A good example is that of homeobox proteins for which NLSs are situated within the DNA-binding homeodomain itself. In many cases, the activity of NLSs and NESs is regulated by their phosphorylation, acetylation, ubiquitylation or methylation (e.g. Chuderland et al., 2008; Kaffman et al., 1998; Madison et al., 2002; Plafker et al., 2004; Smith and Koopman, 2004). Signal activity can also be regulated by NLS concealment, as for the transcription factor, NF-κB, which cannot be recognized by importins until its inhibitory subunits have been removed, or for p53, which conceals its NESs when induced to form a tetramer and activate transcription (e.g. Fagerlund et al., 2005; O’Keefe et al., 2003).
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