p16 and p21 act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16 and p21, namely, tumour promotion through chemotaxis. In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p16 and p21 are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3. Thus, deletion of p16 and p21 reduces CX3CR1 expression, thereby inhibiting Mo-MDSC accumulation in tumours expressing CX3CL1 and suppressing the tumour progression in mice. Notably, blockade of the CX3CL1/CX3CR1 axis suppresses tumour growth, whereas inactivation of CDKs elicits the opposite effect. These findings reveal an unexpected function of p16 and p21 and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727112 | PMC |
http://dx.doi.org/10.1038/s41467-017-02281-x | DOI Listing |
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