Home Faculty and Research Faculty by Name Iswar Hariharan

Iswar Hariharan

Professor of Cell and Developmental Biology*
*C.H. Li Chair in Biochemistry & Molecular Endocrinology

Lab Homepage: http://mcb.berkeley.edu/labs/hariharan/

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Research Interests

Our laboratory is primarily interested in identifying pathways that restrict growth and cell proliferation in vivo. Using screens in Drosophila, we have identified several novel regulators of growth and proliferation. In some instances, the human orthologs of these genes have subsequently found to be mutated in specific cancers.

Current Projects

Identification and characterization of genes that restrict growth and cell proliferation . We have conducted a genetic screen that utilizes mitotic recombination in the Drosophila eye that is capable of identifying mutations that give cells even a subtle growth or proliferative advantage over their wild-type neighbors. We have identified multiple alleles of at least 23 loci and apparent single hits in a number of other loci. We have been characterizing the mutant phenotype and cloning the genes for many of these loci. The genes that we have identified include homologues of known human tumor suppressor genes including PTEN , TSC1 and TSC2 .

Another gene identified in our screen is archipelago . Archipelago is an F-box/WD-repeat containing protein that binds to Cyclin E and targets it for ubiquitin-mediated degradation. Inactivating mutations in archipelago result in delayed exit from the cell cycle and result in excessive cell proliferation. We have identified mutations in the human ortholog in several tumor cell lines, especially those derived from ovarian cancers.

Three other genes that have been identified in our screen are salvador , warts and hippo . Mutations in any of these three genes result in delayed cell cycle exit and impaired apoptosis. The Salvador , Warts and Hippo proteins appear to function in a complex that restricts the levels of Cyclin E and the inhibitor of apoptosis DIAP1. We have identified deletions of the human ortholog of salvador (hWW45) in two kidney cancer cell lines.

We are mapping and cloning many of the other mutations identified in the screen and will evaluate the role of their human orthologs in a variety of cancers.

Selected Publications

Tapon, N., Ito, N., Dickson, B. J., Treisman, J. E., and Hariharan, I. K. (2001). The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105 , 345-355.

Moberg, K. H., Bell, D. W., Wahrer, D. C. R., Haber, D. A., and Hariharan, I. K. (2001). Archipelago regulates Cyclin E levels and is mutated in human cancer cell lines. Nature 413 , 311-316.

Tapon, N., Harvey, K. F., Bell, D. W., Wahrer, D. C. R., Schiripo, T. A., Haber, D. A., and Hariharan I. K.(2002) salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110 , 467-478.

Harvey, K. F., Pfleger, C. M., and Hariharan, I. K. (2003) The Drosophila Mst ortholog, hippo , restricts growth and cell proliferation and promotes apoptosis. Cell 114 , 457-467.

Delalle, I., Pfleger, C. M., Buff, E., and Hariharan, I. K. (2005) Mutations in the Drosophila orthologs of F-actin capping protein alpha- and beta-subunits cause actin accumulation and subsequent retinal degeneration. Genetics 171:1757-1765.

Moberg, K. H., Schelble, S., Burdick, S., and Hariharan I. K. (2005) Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Dev. Cell. 9, 699-710. 

Mills, K., Daish, T., Harvey, K. F., Pfleger, C. M., Hariharan, I. K., and Kumar, S. (2006) The Drosophila melanogaster Apaf-1 homologue ARK is required for most, but not all , programmed cell death. J. Cell Biol. 172:809-815.

Walker, J. A., Tchoudakova, A. V., McKenney, P. T., Brill, S., Wu, D., Cowley, G. S., Hariharan, I. K. and Bernards, A. (2006) Reduced growth of Drosophila neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons. Genes Dev. 20:3311-3323.

Hariharan, I. K. and Bilder, D. (2006) Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu Rev. Genet. 40:335-361.

Last Updated 2007-02-13