Genetic Analysis of ErbB Signaling in C. Elegans
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: In mammals, the ErbB family of genes controls the development of breast tissue. The protein product from these genes form surface membrane receptors that relay growth signals into cells. In many cases of breast cancer, mutations in either ErbB or other genes cause ErbB proteins to become too active or increase in amount. This contributes to the malignancy of the disease by stimulating uncontrolled cell growth. Drugs, such as Herceptin, inhibit ErbB2 (also called Her-2/neu) and are used to block these effects. However, blocking ErbB2 appears to be effective less than half the time. Thus, more information is needed to locate and study the functions of genes that interact with ErbB genes or produce proteins that modulate ErbB2 signaling effects. To rapidly identify and analyze potential human genes that regulate ErbB genes and their protein product, we have chosen the nematode worm, C. elegans, as a model system. C. elegans has one ErbB gene, called let-23, which controls the amount of vulval tissue in these animals. In an analogous manner to the situation in breast cancer, worms that have too much let-23 activity develop too much vulval tissue. This gives us a system and a phenotypic read-out to find other nematode genes that influence let-23. 
 
 
 
 
 
 
 
 In preliminary studies we used a chemical to randomly create mutations in C. elegans, some of which were observed to increase the amount of let-23-dependent vulval tissue. The focus of this project is to determine the identity of two such mutant genes, ear-2 and ear-1, and to characterize how their mutation increases ErbB activity. Most experiments will involve mating worms to each other to create different genetic backgrounds, and using microscopy to examine the amount of vulval tissue in these animals. Some experiments will involve the introduction of recombinant DNA into worms, the use of a laser to surgically kill specific cells, and the analysis of worm DNA for mutations. Since C. elegans has a very short life cycle, this project will allow the rapid generation and identification of mutant genes that increase sensitivity to an ErbB family member. Furthermore, different combinations of mutations can be readily created to examine how they increase or decrease ErbB activity. 
 
 
 
 
 
 
 
 We are encouraged to attempt this project, because previous work in C. elegans led to the first demonstration that the Cbl class of proteins that block ErbB activity. This relationship has now been confirmed in human cells, and importantly, the amount of Cbl protein influences the response of breast cancer cells to therapeutic agents. It might seem surprising that worms can provide a potential model for key events in breast cancer. However, it remains true that at fundamental levels of cell organization and growth control processes, worms and humans share common genes. If successful, this work will translate to a better understanding and treatment of human breast cancer.