MYC accelerates p21(CIP) -induced megakaryocytic differentiation involving early mitosis arrest in leukemia cells.MYC accelerates p21(CIP) -induced megakaryocytic differentiation involving early mitosis arrest in leukemia cells.Muñoz-Alonso MJ, Ceballos L, Bretones G, Frade P, León J, Gandarillas A. J Cell Physiol. 227: 2069–2078 (2012).2012-06-07T22:00:00Z<p style="text-align:justify;"><strong class="ms-rteThemeFontFace-1 ms-rteFontSize-2">​Abstract</strong></p><p style="text-align:justify;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;">p21</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;line-height:0;vertical-align:baseline;top:-0.5em;color:#1c1d1e;">CIP</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;"> is a potent cell cycle inhibitor often up‐regulated in differentiation. Protooncogene MYC induces cell growth and proliferation, inhibits differentiation and represses p21</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;line-height:0;vertical-align:baseline;top:-0.5em;color:#1c1d1e;">CIP</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;">. However, both molecules are involved in processes of polyploidisation, cell size increase, differentiation and senescence. It is unclear why MYC has a dual role in differentiation. We have previously shown that overexpression of p21</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;line-height:0;vertical-align:baseline;top:-0.5em;color:#1c1d1e;">CIP</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;"> in K562 myeloid cells induces megakaryocytic differentiation with polyploidy. We have now investigated the requirements for p21</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;line-height:0;vertical-align:baseline;top:-0.5em;color:#1c1d1e;">CIP</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;"> to block mitosis and induce differentiation in the presence of overactivated MYC. Silencing and over‐expression studies showed that p21</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;line-height:0;vertical-align:baseline;top:-0.5em;color:#1c1d1e;">CIP</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;"> is required to induce differentiation. However, the expression of p21</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;line-height:0;vertical-align:baseline;top:-0.5em;color:#1c1d1e;">CIP</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;"> needs to be transient to irreversibly inhibit mitosis but not DNA replication, what leads to polyploidy. Transient overexpression of p21</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;line-height:0;vertical-align:baseline;top:-0.5em;color:#1c1d1e;">CIP</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;">caused early down‐regulation of mitotic Cyclins and up‐regulation of G1/S Cyclins D and E, changes typical of endoreplication. Interestingly, over‐activation of MYC did not release the proliferative block imposed by p21</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;line-height:0;vertical-align:baseline;top:-0.5em;color:#1c1d1e;">CIP</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;"> and instead, accelerated cell size increase, megakaryocytic differentiation and polyploidisation. Our data suggests that in some systems p21</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;line-height:0;vertical-align:baseline;top:-0.5em;color:#1c1d1e;">CIP</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#1c1d1e;background-color:#ffffff;"> takes part in a mitosis control driving MYC‐induced cellular growth into differentiation.</span><br></p><p><span class="ms-rteForeColor-2"><a href="https://onlinelibrary.wiley.com/doi/full/10.1002/jcp.22935">​[pubmed]</a></span></p>103