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Development ePress online publication date 26 Jan 2005
doi: 10.1242/dev.01670

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Research article

LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism


Peter Cartwright, Cameron McLean, Allan Sheppard, Duane Rivett, Karen Jones, and Stephen Dalton*
* Author for correspondence (e-mail: sdalton{at}uga.edu)

Murine ES cells can be maintained as a pluripotent, self-renewing population by LIF/STAT3-dependent signaling. The downstream effectors of this pathway have not been previously defined. In this report, we identify a key target of the LIF self-renewal pathway by showing that STAT3 directly regulates the expression of the Myc transcription factor. Murine ES cells express elevated levels of Myc and following LIF withdrawal, Myc mRNA levels collapse and Myc protein becomes phosphorylated on threonine 58 (T58), triggering its GSK3{beta} dependent degradation. Maintained expression of stable Myc (T58A) renders self-renewal and maintenance of pluripotency independent of LIF. By contrast, expression of a dominant negative form of Myc antagonizes self-renewal and promotes differentiation. Transcriptional control by STAT3 and suppression of T58 phosphorylation are crucial for regulation of Myc activity in ES cells and therefore in promoting self-renewal. Together, our results establish a mechanism for how LIF and STAT3 regulate ES cell self-renewal and pluripotency.
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