Hippo Limits Cell Growth

Normal development requires a balance between cell proliferation and cell death; moreover, many malignancies involve both excess proliferation and suppression of apoptosis. During Drosophila eye development, cyclin E and DIAP1 ( Drosophila inhibitor of apoptosis protein 1) regulate proliferation and apoptosis: Exit from the cell cycle depends on down-regulation of cyclin E, whereas DIAP1 suppresses apoptosis. Salvador (Sav) and warts (Wts) have also been implicated in regulation of Drosophila development. However, the underlying mechanisms through which they act remain unclear. Two groups, Wu et al. and Harvey et al. , used a combination of genetic and biochemical approaches to identify hippo ( Hpo ) as encoding a protein kinase that interacts with Sav and Wts to regulate cyclin E and DIAP1 activity and limit cell growth. Both groups showed that hpo loss-of-function mutations led to tissue overgrowth associated with both increased cell proliferation and suppression of apoptosis. Cyclin E protein and mRNA were increased (at least partially because of enhanced transcription). DIAP1 protein was also increased; Wu et al. found that Hpo suppressed diap1 transcription, whereas Harvey et al. observed no change in diap1 mRNA but instead found that Hpo promoted DIAP1 degradation. Both groups demonstrated physical and functional interactions among Hpo, Sav, and Wts, suggesting that the three proteins define a common pathway that regulates cell proliferation and cell death. Wu et al. demonstrated that human MST2 (mammalian STE-20-like kinase 2), a stress-activated protein kinase related to Hpo, rescued the Drosophila overgrowth phenotype, suggesting that MST2 could act as a regulator of mammalian cell growth and thus as a tumor suppressor. S. Wu, J. Huang, J. Dong, D. Pan, hippo encodes a STE-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts . Cell 114 , 445-456 (2003). [Online Journal] K. F. Harvey, C. M. Pfleger, I. K. Hariharan, The Drosophila Mst ortholog, hippo , restricts growth and cell proliferation and promotes apoptosis. Cell 114 , 457-467 (2003). [Online Journal]