title: Enhancement of c-Myc degradation by BLM helicase leads to delayed tumor initiation.
abstract: The spectrum of tumors that arise owing to the overexpression of c-Myc and loss of BLM is very similar. Hence, it was hypothesized that the presence of BLM negatively regulates c-Myc functions. By using multiple isogenic cell lines, we observed that the decrease of endogenous c-Myc levels that occurs in the presence of BLM is reversed when the cells are treated with proteasome inhibitors, indicating that BLM enhances c-Myc turnover. Whereas the N-terminal region of BLM interacts with c-Myc, the rest of the helicase interacts with the c-Myc E3 ligase Fbw7. The two BLM domains act as 'clamp and/or adaptor', enhancing the binding of c-Myc to Fbw7. BLM promotes Fbw7-dependent K48-linked c-Myc ubiquitylation and its subsequent degradation in a helicase-independent manner. A subset of BLM-regulated genes that are also targets of c-Myc were determined and validated at both RNA and protein levels. To obtain an in vivo validation of the effect of BLM on c-Myc-mediated tumor initiation, isogenic cells from colon cancer cells that either do or do not express BLM had been manipulated to block c-Myc expression in a controlled manner. By using these cell lines, the metastatic potential and rate of initiation of tumors in nude mice were determined. The presence of BLM decreases c-Myc-mediated invasiveness and delays tumor initiation in a mouse xenograft model. Consequently, in tumors that express BLM but not c-Myc, we observed a decreased ratio of proliferation to apoptosis together with a suppressed expression of the angiogenesis marker CD31. Hence, partly owing to its regulation of c-Myc stability, BLM acts as a 'caretaker tumor suppressor'.
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Suruchika
authors.initials: S
authors.lastname: Chandra
authors.forename: Raina
authors.initials: R
authors.lastname: Priyadarshini
authors.forename: Vinoth
authors.initials: V
authors.lastname: Madhavan
authors.forename: Shweta
authors.initials: S
authors.lastname: Tikoo
authors.forename: Mansoor
authors.initials: M
authors.lastname: Hussain
authors.forename: Richa
authors.initials: R
authors.lastname: Mudgal
authors.forename: Priyanka
authors.initials: P
authors.lastname: Modi
authors.forename: Vivek
authors.initials: V
authors.lastname: Srivastava
authors.forename: Sagar
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C489427:MYC protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C097151:Bloom syndrome protein; D053484:RecQ Helicases
keywords: BLM; Bloom helicase; Colon carcinoma; E3 ligase; Fbw7; c-Myc