LIN-12/Notch proteins are receptors that mediate cell-cell interactions that specify cell fate during animal development. Studies of LIN-12/Notch proteins are directly relevant to understanding the molecular mechanisms underlying two serious and common human diseases. Constitutive activation of LIN-12/Notch _roteins has been associated with the development of certain cancers in human patients and in mammalian models, and the activity of a key component of the LIN-12/Notch signal transduction pathway, presenUin, is central to the development of Alzheimer's disease. Other, less common, diseases have also been associated with aberrations in LIN-12/Notch pathway components. Our work on lin-12 in C. elegans has contributed to the current state of understanding of conserved developmental roles and molecular mechanisms of LIN-12/Notch proteins. This proposal is concerned with identifying and characterizing new genes that influence lin-12 activity in C. elegans. Our first specific aim encompasses new variations on a proven genetic screen, based on suppression of phenotypes associated with constitutive lin-12 activation [lin-12(d) alleles]. Our second specific aim is concerned with the basic characterization of new sel [suppressor/enhancer of lin-12] genes, and our third specific aim is concerned with understanding how the new genes we identify work together. The last two specific aims are involved with the LIN-12-mediated lateral signalling during vulval precursor cell specification.
The fourth aim i s concerned with identifying and characterizing the ligand for LIN-12 in this signalling event, and the fifth aim is concerned with characterizing a gene that may be involved in the interplay between Ras-mediated vulval induction and LIN-12-mediated lateral signalling. When these specific aims are completed, we hope to have identified conserved components and illuminated fundamental mechanisms of the regulation and execution of LIN-12/Notch signalling in animal development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095389-05
Application #
7163547
Study Section
Genetics Study Section (GEN)
Program Officer
Mietz, Judy
Project Start
2003-01-22
Project End
2009-06-30
Budget Start
2007-01-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$175,017
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Chen, Yunting; Greenwald, Iva (2015) hecd-1 modulates notch activity in Caenorhabditis elegans. G3 (Bethesda) 5:353-9
Sallee, Maria D; Greenwald, Iva (2015) Dimerization-driven degradation of C. elegans and human E proteins. Genes Dev 29:1356-61
Greenwald, Iva; Kovall, Rhett (2013) Notch signaling: genetics and structure. WormBook :1-28
Karp, Xantha; Greenwald, Iva (2013) Control of cell-fate plasticity and maintenance of multipotency by DAF-16/FoxO in quiescent Caenorhabditis elegans. Proc Natl Acad Sci U S A 110:2181-6
de la Cova, Claire; Greenwald, Iva (2012) SEL-10/Fbw7-dependent negative feedback regulation of LIN-45/Braf signaling in C. elegans via a conserved phosphodegron. Genes Dev 26:2524-35
Li, Ji; Greenwald, Iva (2010) LIN-14 inhibition of LIN-12 contributes to precision and timing of C. elegans vulval fate patterning. Curr Biol 20:1875-9
Dunn, Cory D; Sulis, Maria Luisa; Ferrando, Adolfo A et al. (2010) A conserved tetraspanin subfamily promotes Notch signaling in Caenorhabditis elegans and in human cells. Proc Natl Acad Sci U S A 107:5907-12
Choi, Min Sung; Yoo, Andrew S; Greenwald, Iva (2010) sel-11 and cdc-42, two negative modulators of LIN-12/Notch activity in C. elegans. PLoS One 5:e11885
Myers, Toshia R; Greenwald, Iva (2007) Wnt signal from multiple tissues and lin-3/EGF signal from the gonad maintain vulval precursor cell competence in Caenorhabditis elegans. Proc Natl Acad Sci U S A 104:20368-73
Katic, Iskra; Greenwald, Iva (2006) EMB-4: a predicted ATPase that facilitates lin-12 activity in Caenorhabditis elegans. Genetics 174:1907-15

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