Thursday, October 10, 2013

Key Molecule Involved in Cell Division Could be a Novel Therapeutic Target

Regulation of cell division is essential for developing organisms but can lead to harmful tumor growth when the process is dysregulated. Our expanding knowledge of how this process is regulated has lead to novel therapeutic targets based on the blockade of cell division or mitosis. A paper in the current issue of The Proceedings of the National Academy of Sciences describes the collaborative efforts of Spanish and French scientists to decipher the role of the protein Greatwall in mammalian cell division.

Cell in prometaphase
by Roy van Heesbeen

Previous to this report, Greatwall was shown to regulate cell division in invertebrates such as the Drosophilla melanogaster fly and its biochemistry has been characterized in Xenopus. The current work describes the generation of the first mammalian genetic model of this protein using mice. The authors found that cells lacking Greatwall are not capable of adequately dividing themselves even though they enter mitosis with normal kinetics. The deviation from normal cell division occurs after the nuclear envelope breaks down exposing nuclear components such as chromosomes to the cytoplasm and the enzyme activities localized there. Without Greatwall the DNA does not condense to form the correct structures and cell division is halted at prometaphase.



The potential therapeutic capacity of Greatwall is enhanced because it acts by blocking the function of PP2A, a frequently altered tumor suppressor. Therefore, inhibition of Greatwall could slow down cell division and reactivate a tumor suppressor that has been shown to be capable of inhibiting many oncogenic pathways involved in the development of cancer. The search now begins for compounds capable of inhibiting Greatwall and understanding which types of cancer would most benefit from treatment with a Greatwall inhibitor.

The title of the PNAS article is: 'Greatwall is essential to prevent mitotic collapse after nuclear envelope breakdown in mammals'