The level of pro-caspase-8 expression did not change during this process, however, we did detect a modest accumulation of the DED domains among differentiating and non-proliferative cells. We also detected the DEDs of caspase-8 at the centrosome, and this persisted during reorganization of the microtubules upon differentiation. To evaluate whether the DEDs of caspase-8 influence cell differentiation, we next examined myeloid differentiation, in which caspase-8 has been implicated in vivo. Phorbol-ester-induced differentiation of U937 cells resulted in DED accumulation, as determined via immunoblot analysis with a monoclonal antibody to the DEDs of caspase-8. No caspase-8 DEDs were observed in differentiated U937 cells in which caspase-8 expression was silenced. Differentiation of the U937-shC8 cells was consistently compromised relative to control cells expressing caspase-8, both, by expression of the macrophage marker CD11b when scored by flow cytometry or by morphological criteria. Importantly, re-expression of the DEDs was sufficient to rescue the differentiation process. Together, these results support the Albaspidin-AP notion that the DEDs of caspase-8 regulate terminal differentiation. In this study, we characterize a new function for the death effector domains of caspase-8 in cell cycle regulation. First, we find that caspase-8 DEDs Pinoresinol-diglucoside accumulate in cells undergoing terminal differentiation. Silencing of caspase-8 disrupts or delays differentiation, while reintroduction of DEDs restores differentiation potential. We further report that DED expression is sufficient to impair tumor growth and cell proliferation, promoting mitotic defects that foster cell death or cell cycle arrest and terminal differentiation. Finally, we demonstrate that these events require a critical lysine in a microtubule binding motif in the second DED. These observations together suggest that caspase-8 DEDs function as a tumor suppressor, acting as an antiproliferation and differentiation-inducing element.It is tempting to speculate that this type of mechanism may act in some spontaneously regressing tumors, such as stage IV-S neuroblastoma, however, such a mechanism would be co-dependent upon other classic tumor suppression pathways, including p53 and p21.