INT6 May Influence Breast Cancer Formation by Regulating the 26S Proteasome
Abstract
Inactivation of int6 has been linked to breast cancer formation, but its molecular function and precise role in tumorigenesis are largely unknown. This project tests the hypothesis that int6 is a tumor suppressor gene, regulating the proteasome to mediate genetic stability and cell division. The specific aims of this proposal are to determine whether disrupting Int6 function can influence (1) proteasome functioning and (2) chromosome segregation in human cells. I have generated siRNAs that successfully knock-down Int6 expression in HeLa and human mammary epithelial cells, and HeLa cells with reduced Int6 expression display mitotic defects. The next step is to generate stable human mammary cells with reduced Int6 level to carry out detailed studies on chromosomal segregation and proteasome functioning. In addition, I engaged in mechanistic study in S. pombe to better understand the regulation of the proteasome by Int6. Like many proteasome subunits, Int6 contains a PCI domain, and it may play an important role in influencing tumorigenesis. I have identified an essential residue in the PCI domain, and have validated its importance in Int6 and a proteasome subunit Rpn7. Furthermore, my data suggests that nuclear import of proteasome subunits might involve an importin alpha-independent mechanism, specifically mediated by the importin beta Kap 123. In the future, I will next examine whether Int6 regulates Kapl23 in both yeast and humans.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2005
- Accession Number
- ADA436962
Entities
People
- Eric Chang
- Zhe Sha
Organizations
- Baylor College of Medicine