Tumor Suppressor eIF3f Inhibits Translation by Regulating rRNA Degradation
Jiaqi Shi, Fushi Wen, Renyuan Zhou, Alex Shen, Andrew Choi. University of Arizona, Tucson, AZ; Fifth People's Hospital of Shanghai, Shanghai, China
Background: Deregulated translation plays an important role in human cancer. Prominent nucleoli have been recognized to be one of the key features of many malignant cells in pathology for decades, which implicates increased ribosome generation and translation. However translational control mechanisms in cancer development are poorly understood. We were the first to report a translation initiation factor eIF3f as a potential tumor suppressor in pancreatic cancer and melanoma. Decreased expression and loss of heterozygosity of eIF3f is found in majority of the pancreatic cancer cases. Knockdown of eIF3f expression in normal pancreatic epithelial cells transformed these cells to malignant cells. Restoration of eIF3f expression in cancer cells led to apoptosis.
Design: In the present study, we used a bicistronic luciferase reporter assay to investigate the specific effect of eIF3f on cap-dependent and cap-independent translation. Using quantitative real time RT-PCR analysis, we assessed whether eIF3f regulates ribosomal RNA (rRNA) degradation. We have also used immunofluorescent and molecular beacon assay to determine the subcellular localization of eIF3f protein and its relationship with cytoplasmic granules that involved in RNA degradation and rRNAs.
Results: We found that eIF3f inhibited both cap-dependent and cap-independent translation. We also demonstrated that eIF3f promotes rRNA degradation. Therefore in cancer cells, decreased eIF3f expression stabilized rRNA and thus promoted translation. We further showed that eIF3f co-localized with some cytoplasmic granules that are involved in RNA degradation (P body and stress granules) and rRNA.
Conclusions: Tumor suppressor eIF3f inhibits translation by enhancing rRNA degradation. Our findings established a new mechanism of rRNA decay regulation mediated by eIF3f and suggested that the tumor suppressive function of eIF3f may link to increased rRNA degradation and impaired translation.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 284, Monday Morning