Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1

• DOI: 10.1073/pnas.1119167109
• Publication Date: 2012-01-11T05:30:41Z
• Authors: Levi J. Beverly; William W. Lockwood; Parag P. Shah; Hediye Erdjument-...; Harold Varmus
• Keywords: 0301 basic medicine; Cytoplasm; Lung Neoplasms; Protein Stability; Lysine; Autophagy-Related Proteins; Adenocarcinoma of Lung; Apoptosis; Cell Cycle Proteins; Adenocarcinoma; Models, Biological; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; Protein Transport; 03 medical and health sciences; Cell Transformation, Neoplastic; Cell Line, Tumor; Animals; Humans; Carrier Proteins; Adaptor Proteins, Signal Transducing; Protein Binding

We have previously shown that all six members of the anti-apoptotic BCL2 gene family can cooperate with (myelocytomatosis oncogene) MYC in a mouse model of leukemia, but three of them are significantly less potent contributors to leukemogenicity than the other three. The protein encoded by one of these less potent genes, BCL2L10/BCLb, was recently shown to vary dramatically in many primary human cancers by immunohistochemistry, and the protein levels were inversely correlated with survival in patients with several cancer types. We examined BCLb mRNA in a panel of human cancer cell lines and did not observe the extensive variation in mRNA that would be required to explain the vast differences in protein levels. We found that the levels of BCLb protein diminish quickly after inhibition of protein synthesis with cycloheximide, so we searched for interacting proteins that might affect posttranslational stability of BCLb. Using a variety of approaches, including immunoaffinity and mass spectrometry, we identified a protein, Ubiquilin1 (Ubqln), that specifically interacts with BCLb, and not with other anti-apoptotic BCL2-like proteins. Ubqln stabilizes BCLb protein, while also promoting monoubiquitination on multiple lysine residues and relocation to the cytosol. Furthermore, primary lung adencarcinomas have more Ubqln mRNA than normal adjacent lung tissue, and higher Ubqln mRNA levels are associated with shorter survival of lung cancer patients, suggesting that potentiation of the anti-apoptotic potential of BCLb through regulation of its stability by Ubqln may be an important factor in tumor progression.