Identification and characterization of novel E3 ubiquitin ligases involved in cell communication and cancer
The ubiquitin system is a critical modulator of a wide range of cellular processes, including protein degradation, DNA repair, gene transcription, cell-cycle control, and intercellular communication. The importance of ubiquitination is reflected by the fact that the human proteome has been estimated to contain over 600 E3 ubiquitin ligases. The ubiquitin system is frequently altered in cancer cells, and several known E3 ubiquitin ligases are key oncogenes or tumor suppressors, representing potential targets in cancer therapy. The objective of this Master’s project is to identify and functionally characterize E3 ubiquitin ligases involved in intercellular communication and cancer pathogenesis.
Cells in tissues communicate with their adjacent cells by exchanging ions and small molecules via intercellular channels. Such channels assemble into specialized plasma membrane domains known as gap junctions. The channels are a composed of a family of transmembrane proteins called connexins. In humans, the connexin protein family constitutes 21 members, of which the most ubiquitously expressed is called connexin43 (Cx43). Gap junctions enable neighboring cells to communicate both electrically and metabolically, and they have essential roles in coordinating the activities of individual cells in tissues. Connexins have important roles in controlling cell growth and differentiation, and several lines of evidence suggest that dysregulation of connexins and intercellular communication via gap junctions is involved in cancer pathogenesis. In line with this notion, multiple members of the connexin protein family have been shown to act as tumor suppressor proteins, and they are frequently downregulated during cancer development, resulting in loss of intercellular communication.
There is increasing evidence that ubiquitination of connexins has an important role in regulating intercellular communication via gap junctions. Moreover, many growth factors, oncogenes, and tumor promoters are potent inducers of connexin ubiquitination and degradation, resulting in the loss of gap junctions at the plasma membrane. Dysregulation of connexin ubiquitination may play an important role in the loss of intercellular communication during cancer development, which may have considerable clinical relevance.
This Master’s project aims to identify and functionally characterize novel E3 ubiquitin ligases involved in regulation of connexin ubiquitination and degradation. The project further aims to elucidate how dysregulation of these processes may contribute to aberrant expression of connexins and loss of intercellular communication via gap junctions during cancer pathogenesis.
The Master’s student will learn various methods, including DNA/siRNA transfection, RNA interference, confocal microscopy, cell-cell communication assays, co-immunoprecipitation, western blotting and cell culture.
The project will be carried out at The Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital (http://www.ous-research.no/molecularoncology/). Our department currently has approximately 40 members, including 10 PhD students and four Master’s students. The Master’ student on this project will work in close collaboration with PhD students and scientists in the department.
Supervisors: Edward Leithe, Ragnhild A. Lothe