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Through genetic screening in Drosophila, a novel tumor suppressor gene, HIPPO (Hpo), was identified. The N-terminal kinase domain of hpo belongs to the Ste20 family Ser/Thr kinases which are divided into the p21-activated kinases and germinal center kinase subfamilies. During the developmental stage, Hpo regulates apoptosis via autonomouse downregulation of DIAP1 protein (Drosophila inhibitor of apoptosis 1). It interacts with sav and phosphorylates sav. Phosphorylated sav increases the ability of hpo to promote further phosphorylation of wts. Mutations of Sav and deficiency of Wts has been implicated in cancer cell lines and murine cancer models. It is hypothysized that Hpo may promote apotosis and suppress malignant growth.
Hpo also has 60% identity to human MST2 and 58% identity to human MST1. Although overexpression of MST1 promotes apoptosis, the physiological function of MST2 is still unknown. The expression of human MST2 in hpo mutant corrected or suppressed the overgrowth phenotype, providing further evidence that MST2 is likely to be a tumor suppressor gene.
This technology provides a method for screening apoptosis modulators using HIPPO or MST2. It also provides a potential novel therapeutic target.
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