1) Regulation of growth in imaginal discs during development
Over the last fifteen years, we have conducted a genetic screen that has led to the identification of many genes that restrict tissue growth and cell proliferation in vivo. Following mutagenesis, we generated flies with eyes that contain both wild-type tissue (marked red) and mutant tissue (marked white). By comparing the relative representation of the two types of tissue we can identify mutations that allow mutant cells to outgrow their wild type neighbors.
|The mutant eye (right image) shows an increase in the relative representation of mutant tissue (white) when compared to the control (left image).|
Once we identify the mutant flies, we map the mutation and characterize the mutated gene at the molecular level. Further studies of the encoded protein usually provide clues as to how this gene functions to regulate tissue growth. Our eventual aim is to understand the cellular circuitry that regulates the growth process.
Genes identified in our screen include the orthologs of the genes mutated in the human disease tuberous sclerosis (Tsc1 and Tsc2), pten, components of the RTK/Ras pathway (e.g. Gap1, argos, capicua ) as well as many genes that function to regulate growth in ways that are still not well understood. One of the genes that we have characterized archipelago, encodes a protein that facilitates the destruction of Cyclin E and Myc. Another set of three genes (salvador, warts and hippo) constitute a novel pathway that restricts tissue growth. For the human orthologs of archipelago and salvador, we identified mutations in cancer cell lines. We and others have identified mutations in the human ortholg of archipelago (hCdc4, FBW7) in primary human tumors.
Some of our papers :
Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK (2001) The Drosophila tuberous sclerosis complex gene homologs restrict growth and cell proliferation. Cell 105:345-55 (PubMed Link)
Moberg KH, Bell DW, Wahrer DC, Haber DA, Hariharan IK (2001) Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413:311-6 (PubMed Link)
Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA, Haber DA, Hariharan IK (2002) salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110:467-78 (PubMed Link)
Harvey KF, Pfleger CM, Hariharan (2003) The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114:457-67 (PubMed Link)
Moberg KH, Mukherjee A, Veraksa A, Artavanis-Tsakonas S, Hariharan IK (2004) The Drosophila F-box protein regulates dMyc protein levels in vivo. Current Biology 14:965-74 (PubMed Link)
Moberg KH, Schelble S, Burdick SK, Hariharan IK (2005) Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Developmental Cell 9:699-710 (PubMed Link)
Pellock BJ, Buff E, White K, Hariharan IK (2007) The Drosophila tumor suppressors Expanded and Merlin differentially regulate cell cycle exit, apoptosis and Wingless signaling. Developmental Biology 304:102-15 (PubMed Link)
Tseng AS, Tapon N, Kanda H, Cigizoglu S, Edelman L, Pellock B, White K, Hariharan IK (2007) Capicua regulates cell proliferation downstream of the receptor tyrosine kinase/ras signaling pathway. Current Biology 17:728-33 (PubMed Link)
Pfleger CM, Harvey KF, Yan H, Hariharan IK (2007) Mutation of the gene encoding the ubiquitin activating enzyme Uba1 causes tissue overgrowth in Drosophila. Fly (Austin) 1:95-105 (PubMed Link)
Herz HM, Madden LD, Chen Z, Bolduc C, Buff E, Gupta R, Davuluri R, Shilatifard A, Hariharan IK, Bergmann A (2010) The H3K27 demethylase dUTX is a suppressor of Notch- and Rb-dependent tumors in Drosophila. Mol. Cell. Biol. 30:2485-97. (PubMed Link)
Kanda H, Nguyen A, Chen L, Hariharan IK (2013) The Drosophila ortholog of MLL3 and MLL4, trithorax related, functions as a negative regulator of tissue growth. Mol. Cell. Biol. 33:1702-10. (PubMed Link)
and...some review articles:
Hariharan IK, Bilder D (2006) Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila Annual Review of Genetics 40:335-61 (PubMed Link)
Hariharan IK (2006) Growth regulation: a beginning for the hippo pathway Current Biology 16:R1037-9 (PubMed Link)