Inhibiting Greatwall may provoke mitotic collapse and suppress tumor growth.
Emerging research from the Spanish National Cancer Research Centre (CNIO) sheds new light on the relationship between the protein kinase Greatwall and successful cell division and suggests the protein as a novel oncogenic target.
Greatwall was originally identified in Drosophila as a protein required for DNA condensation and normal progression through mitosis. To date, most Greatwall studies have used Drosophila models. The CNIO study, which was performed in collaboration with researchers from the National Centre for Scientific Research (CNRS), uses a murine conditional knockout model to show that Greatwall is needed in mammals to prevent mitotic collapse after nuclear envelope breakdown (NEB).
The study, being led by CNIO’s Marcos Malumbres, shows that the mammalian ortholog of Greatwall, Mastl (microtubule-associated serine/threonine kinase-like protein), functions by inhibiting PP2A phosphatase complexes which counteract Cdk-dependent phosphorylation reactions required for mitosis. According to Malumbres, “Greatwall is exported to the cytoplasm in a Cdk-dependent manner before NEB, thus protecting mitotic phosphates from phosphatase activity.”
Interestingly, the results show Greatwall null cells enter into the mitotic state successfully. However, after NEB occurs, so too does mitotic collapse. The timing here is key; NEB subjects cells to mitotic stress and provides a moment in which nuclear chromatin are exposed to cytoplasmic phosphatases. Without the presence of Greatwall to inhibit these phosphatases, the cell is unable to continue successfully through mitosis.
While there are a number of mitotic proteins currently being explored as anticancer targets, the new research suggests that Greatwall may offer more therapeutic advantages than its counterparts. Greatwall acts by blocking the function of the PP2A phosphatase, a tumor suppressor frequently altered in human cancer. This suggests that the inhibition of Greatwall could simultaneously slow down cell division and reactivate tumor suppressor PP2A, a protein capable of inhibiting many of the oncogenic molecular pathways involved in cancer development.
Dr. Malumbres and colleagues are extremely excited about the possibilities Greatwall offers, “Therapeutics development is currently in need of novel targets that attack tumors in a different way. Greatwall offers new strategies amongst which can be found reactivating a very important tumor suppressor, something for which there are no direct therapies at the moment.”