2023-07-11 11:54:10
The intestinal epithelium is a very dynamic tissue, constantly renewed, thanks to the proliferation and differentiation of intestinal stem cells. Maintaining the balance between proliferation and differentiation is crucial for the development and maintenance of tissue integrity. Indeed, alterations of the latter can be the cause of developmental abnormalities as well as tumor transformation. The study of the mechanisms involved in the specification and differentiation of stem cells is therefore essential to better understand tissue homeostasis.
p57/Kip2 is an inhibitor of cyclin/CDK complexes belonging to the Cip/Kip family. Due to its CDK inhibitory activity, p57 acts as a negative regulator of the cell cycle and is therefore a potential tumor suppressor gene. Unlike other CDK inhibitors, p57 plays a crucial role during development, which is illustrated by the perinatal lethality of p57KO mice. p57 is also the most frequently mutated or repressed gene in Beckwith-Wiedemann syndrome (BWS), characterized by developmental abnormalities and tumor predisposition during childhood. The generation of a knock-in mouse model (p57CK-) in which p57 no longer binds cyclin/CDK complexes, has made it possible to highlight the essential role played by this molecule in intestinal development, independently of the inhibition of CDKs.
Two types of intestinal stem cells have been described, CBC proliferative stem cells, responsible for the constant renewal of the epithelium, and so-called reserve +4 (Hopx+) stem cells, mobilized in the event of damage in order to regenerate the tissue.
Through genetic tracing experiments live in mice, the scientists demonstrated that p57 is involved in maintaining the quiescence of reserve stem cells, independently of CDK inhibition. Indeed, p57KO mice show increased proliferation in the intestinal crypts due to an amplification of progenitor cells and Hopx+ stem cells, whereas CBCs are not affected.
Transcriptomic analysis performed on sorted intestinal stem cells revealed major changes in gene expression in the absence of p57. The scientists were able to demonstrate that p57 is capable of inhibiting the transcriptional activity of Ascl2, a key transcription factor for homeostasis and regeneration of the intestinal epithelium, via the formation of a repressor complex with newly identified p57 partners: HDAC7 and mSin3a.
This work has therefore shed light on a new function of p57 in intestinal stem cells during development and might explain the role of p57 in intestinal tumorigenesis.
© Justine Creff
Figure: Schematic representation of the role of p57 in intestinal stem cells. p57 controls the proliferation of Hopx+ stem cells by binding to Ascl2 and inhibiting its transcriptional activity via the formation of a repressor complex present on the target promoters of Ascl2.
Learn more:
p57Kip2 acts as a transcriptional corepressor to regulate intestinal stem cell fate and proliferation. . . . Justine Creff, Ada Nowosad, Anne Prel, Anne Pizzoccaro, Marion Aguirrebengoa, Nicholas Duquesnes, Caroline Callot, Thomas Jungas, Christine Dozier and Arnaud Besson. Cell Reports (2023).
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#Identification #function #p57Kip2 #transcriptional #regulation
