Uncoupling of the Hippo and Rho pathways allows megakaryocytes to escape the tetraploid checkpoint

p53 shades of Hippo

“…Activates p53 in response to mitotic stress 53,[142][143][144]149 Activates p53 in response to oncogenic Ras 117,118 Activates p53 in response to excess cholesterol 156 Activates p53 during mESC differentiation 52 YAP Loss of YAP induces p53 145,147,148 YAP represses ΔNp63 to inhibit lung cancer squamous cells transdifferentiation. 182 YAP-p73 promotes apoptosis 106,108-110, 132-134, 136,183 Yki inactivation induces Dmp53 119 p63 inhibits p73-YAPdependent apoptosis 22,137 YAP-tyr357-p73 is a marker for well differentiated HCC 85 Yki binds Dmp53 to promote apoptosis 131 YAP positively regulates p63 in epidermal stem cells 66 Locus is amplified in p53 null tumors [75][76][77]184,185 YAP positively regulates p63 in airway epithelium 71 p53 and YAP antagonistically regulate FOXM1 [186][187][188] YAP-p63 block differentiation in HNSCC 86 p53 transactivates 14-3-3σ, which inhibits YAP/TAZ 124,125 Binds p63 and prevents its degradation 88,89 YAP and p53 cooperate in apoptosis and senescence [126][127][128] Hyperactivation of YAP/TAZ induces p53 152,154 YAP and mutp53 cooperate in transformation 33,82 Mutp53 induces miRs that tar...…”

“…143 Indeed megakaryocytes, naturally occurring polyploid cells, in which polyploidization is needed for platelet formation, escape the p53-LATS axis by uncoupling RHOA activity from Hippo signaling. 144 Thus, induction of LATS2 in response to ploidy aberrations enables simultaneous activation of a protective p53-dependent growth arrest and inactivation of YAP/TAZ pro-proliferative signals.…”

BMP2K dysregulation promotes abnormal megakaryopoiesis in acute megakaryoblastic leukemia

“…Methotrexate is used for therapy of ALL and AMKL [16,17]. Etoposide triggers mitochondrial damage, caspase activation and cell death in megakaryocytes [18] and induce genotoxic stress by activating the Hippo-p53 axis in megakaryocytes [19]. All these compounds efficiently suppressed proliferation of control cells whereas BMP2K overexpression antagonized the effect of all these compounds and improved cell proliferation (Fig.…”

The Hippo-p53 pathway in megakaryopoiesis

“…10 Given that RhoA activity is low in megakaryocytes undergoing polyploidization, one might predict that the Hippo-p53 pathway would be activated and prevent the process. However, a new study by Roy et al published 16 The critical observation is that, despite the presence of a functional Hippo-p53 pathway, low RhoA activation in megakaryocytes fails to activate the tetraploid checkpoint and instead allows for endomitosis. In addition, the sustained activation of YAP contributes to megakaryopoiesis by increasing expression of mitochondrial genes including PGC1α, which contributes to mitochondrial biogenesis.…”

“…18,19 In this new report, knockdown of p53 was shown to result in a modest, but significant, increase in MK polyploidization as well as increased numbers of pro-platelet forming cells and cytoplasmic maturation. 16 Perhaps the most surprising finding of Roy et al is the link between YAP and expression of the mitochondrial biogenesis regulator PGC1α during megakaryocyte differentiation and polyploidization. Although YAP regulated genes are generally thought to induce proliferation and survival of cells in the absence of Hippo-p53 activation, knockdown of YAP had no effect on polyploidization or apoptosis of megakaryocytes but rather the reduction of YAP did lead to decreased proplatelet formation and reduced mitochondrial mass, which the authors demonstrate is a notable feature of polyploid megakaryocytes.…”