Tumor suppressor genes (TSGs) play a major role in the pathogenesis of human cancers. Here, a new TSG designated hippo (hpo) is described, and the human homolog mst2 is identified as an additional TSG. hpo as a gene that regulates both cell proliferation and cell death in Drosophila, and encodes a Ste-20 family protein kinase that binds to and phosphorylates the tumor suppressor protein Salvador (Sav), which is known to interact with the Warts (Wts) protein kinase. Loss of hpo results in elevated transcription of the cell cycle regulator cyclin E and the cell-death inhibitor diap1, leading to increased proliferation and reduced apoptosis. Further, hpo, sav, and wts define a pathway that regulates diap1 at the transcriptional level. A human homolog of hpo completely rescues the overgrowth phenotype of Drosophila hpo.sup.- mutants.