Matthews, J.R., Sansom, O.J. and Clarke, A.R. (2011) Absolute requirement for STAT3 function in small-intestine crypt stem cell survival. Cell Death and Differentiation, 18(12), pp. 1934-1943. (doi: 10.1038/cdd.2011.77)
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Publisher's URL: http://dx.doi.org/10.1038/cdd.2011.77
Abstract
The transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated in human cancers. Interestingly, STAT3 also maintains the pluripotency and self-renewal of murine embryonic stem cells, and several tissue stem cell types. To investigate whether STAT3 also maintains the small-intestine crypt stem cell, we conditionally inactivated a Floxed Stat3 allele (Stat3(fl)) in murine small-intestine crypt stem cells. Following Cre recombinase expression, apoptosis increased in Stat3(fl/-) experimental crypts relative to Stat3(wt/-) controls before declining. Control Stat3(wt/-) mice carrying a Flox-STOP LacZ reporter transgene stably expressed LacZ after Cre induction. In contrast, Stat3(fl/-) intestine LacZ expression initially increased modestly, before declining to background levels. Quantitative PCRs revealed a similar transient in recombined Stat3(fl) allele levels. Long-term bromodeoxyuridine labelling directly demonstrated that functional STAT3 is required for +4 to +6 region label-retaining small-intestine stem cell survival. Rapid clearance of recombined Stat3(fl/-) cells involves apoptosis potentially induced by elevated c-Myc in non-recombined cells and involves elevated p53 expression and caspase 3 activation. Intriguingly, Stat3(fl/-) intestine recombination triggered dramatically upregulated polycomb transcriptional repressor Bmi1 - potentially accelerating recombined crypt repopulation. In summary, STAT3 activity is absolutely required for small-intestine crypt stem cell survival at both the +4 to +6 label-retaining and crypt base columnar cell locations.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Sansom, Professor Owen |
Authors: | Matthews, J.R., Sansom, O.J., and Clarke, A.R. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | Cell Death and Differentiation |
ISSN: | 1350-9047 |
ISSN (Online): | 1476-5403 |
Published Online: | 03 June 2011 |
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