RESUMO
The 26S proteasome is a large multi-protein complex that functions to degrade proteins tagged with multi-ubiquitin chains. There are several mechanisms employed by the cell to ensure the efficient delivery of multi-ubiquitinated substrate proteins to the 26S proteasome. This is not only important to ensure the degradation of damaged and misfolded proteins, but also the regulated turnover of critical cell regulators. This discussion will concentrate on what is known about the recognition and delivery of ubiquitinated substrate proteins to the 26S proteasome.
Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Animais , Humanos , Chaperonas Moleculares/metabolismo , Ligação ProteicaRESUMO
Epithelial ovarian cancer (EOC), the leading cause of death from gynecological malignancy, is a poorly understood disease. The typically advanced presentation of EOC with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases are hallmarks of the disease. These features relate to the biology of the disease, which is a principal determinant of outcome. EOC arises as a result of genetic alterations sustained by the ovarian surface epithelium (OSE; ref. 3). The causes of these changes are unknown but are manifest by activation of oncogenes and inactivation of tumor-suppressor genes (TSGs). Our analysis of loss of heterozygosity at 11q25 identified OPCML (also called OBCAM), a member of the IgLON family of immunoglobulin (Ig) domain-containing glycosylphosphatidylinositol (GPI)-anchored cell adhesion molecules, as a candidate TSG in EOC. OPCML is frequently somatically inactivated in EOC by allele loss and by CpG island methylation. OPCML has functional characteristics consistent with TSG properties both in vitro and in vivo. A somatic missense mutation from an individual with EOC shows clear evidence of loss of function. These findings suggest that OPCML is an excellent candidate for the 11q25 ovarian cancer TSG. This is the first description to our knowledge of the involvement of the IgLON family in cancer.