Discovery of the First Endogenous Gain of Function Mutation in Drosophila RAS1 as a Dominant Suppressor of Apoptosis

<p>The development of multicellular organisms requires a tight coordination of cell proliferation, cell differentiation and cell death in order to correctly specify cell fate and number. According to the trophic theory of survival, this is achieved in part by a competition between cells in a tissue for a limited number of extracellular survival factors. Cells that do not receive sufficient quantities of these survival cues engage a default cell death program and are thereby eliminated. This 'social control' of cell survival ensures the integrity of tissues by matching the correct number of different cell types to each other. Apoptosis is one morphologically distinct, genetically programmed form of cell death by which cells in an organism are efficiently and rapidly removed. The proper execution of apoptosis is therefore critical to normal development and homeostasis in metazoans and defects in the regulation of apoptosis is known to contribute to the etiology of several major diseases. Initial insights into the complex molecular networks that regulate apoptosis derived largely from elegant genetic analyses of invertebrate model organisms. These early studies identified several genes critical for the execution of the apoptosis and established an evolutionarily conserved core cell death pathway. To further elucidate the molecular mechanisms underlying the control of apoptosis, we conducted several mutagenesis screens in Drosophila melanogaster to identify genes that can modulate cell death phenotypes. One particularly interesting mutant isolated in these screens was recovered as a strong, specific and dominant suppressor of cell death induced by the RHG protein hid. We demonstrate that this mutant is a gain-of-function allele of ras85D (ras1), the Drosophila homolog of mammalian oncogenes H-ras, K-ras and N-ras. We further establish that this viable allele, rasR68Q, contains a mutation in the Switch II region of Ras and that it produces a GTPase protein with diminished enzymatic activity. RasR68Q is the first endogenous gain-of-function ras1 allele to be identified in Drosophila and represents one of very few hypermorphic Ras mutations compatible with organismal viability to be isolated.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2008

Author dc:creator

• Gafuik, Christopher

Contributors dc:contributor

• Hermann Steller

• apoptosis
• cell survival
• Drosophila
• ras1 gain-of-function
• RHG proteins
• RasR68Q
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/193

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1196