title: Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1.
abstract: 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.
authors.affiliation: Cancer Biology and Genetics Section, Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Levi.Beverly@Louisville.edu
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.forename: Parag P
authors.initials: PP
authors.lastname: Shah
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Harold
authors.initials: H
authors.lastname: Varmus
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D016019:Survival Analysis; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; C117144:BCL2-like 10 protein; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C107792:UBQLN1 protein, human; D014452:Ubiquitins; D008239:Lysine