Abstract
The MYC protein is a transcription factor with oncogenic potential controlling fundamental cellular processes such as cell proliferation, metabolism, differentiation, and apoptosis. The MYC gene is a major cancer driver, and elevated MYC protein levels are a hallmark of most human cancers. We have previously shown that the brain acid‐soluble protein 1 gene (BASP1) is specifically downregulated by the v‐myc oncogene and that ectopic BASP1 expression inhibits v‐myc‐induced cell transformation. The 11‐amino acid effector domain of the BASP1 protein interacts with the calcium sensor calmodulin (CaM) and is mainly responsible for this inhibitory function. We also reported recently that CaM interacts with all MYC variant proteins and that ectopic CaM increases the transactivation and transformation potential of the v‐Myc protein. Here, we show that the presence of excess BASP1 or of a synthetic BASP1 effector domain peptide leads to displacement of v‐Myc from CaM. The protein stability of v‐Myc is decreased in cells co‐expressing v‐Myc and BASP1, which may account for the inhibition of v‐Myc. Furthermore, suppression of v‐Myc‐triggered transcriptional activation and cell transformation is compensated by ectopic CaM, suggesting that BASP1‐mediated withdrawal of CaM from v‐Myc is a crucial event in the inhibition. In view of the tumor‐suppressive role of BASP1 which was recently also reported for human cancer, small compounds or peptides based on the BASP1 effector domain could be used in drug development strategies aimed at tumors with high MYC expression.
Highlights
The transcription factor avian myelocytomatosis viral oncogene homolog (MYC) constitutes the central hub of a regulatory network controlling the expression of thousands of genes
Primary quail embryo fibroblasts (QEF) and QEF transformed by the v-myc (QEF/replication-competent avian sarcoma leukosis virus vector (RCAS)-avian myelocytomatosis virus 29 (MC29)), vfos (QEF/avian retrovirus NK24 (NK24)), v-jun (QEF/avian sarcoma virus 17 (ASV17)), v-src (QEF/ Rous sarcoma virus (RSV)), or v-myc/v-mil (QEF/avian carcinoma virus MH2 (MH2)) oncogenes were generated by infection with the corresponding retroviruses and grown as described (Hartl et al, 2009)
Cell extracts were prepared from QEF and from QEF transformed by the v-myc, v-fos, v-jun, v-src, or v-mil/v-myc oncogenes
Summary
The transcription factor MYC constitutes the central hub of a regulatory network controlling the expression of thousands of genes. MYC is a master regulator of fundamental cellular processes such as growth, proliferation, differentiation, metabolism, pluripotency, and apoptosis (Conacci-Sorrell et al., Abbreviations AML, acute myeloid leukemia; AR, androgen receptor; ASV17, avian sarcoma virus 17; BASP1, brain acid-soluble protein 1; CALM, calmodulin (gene); CaM, calmodulin (protein); CaM-ag., calmodulin agarose; CAP-43, cortical cytoskeleton-associated protein 23 alias BASP1; CHX, cycloheximide; CoIP, co-immunoprecipitation; ED, effector domain; FOS, Finkel–Biskis–Jenkins murine osteosarcoma oncogene; GST, glutathione S-transferase; HA, hemagglutinin; HEK-293T, human embryonic kidney 293 cells (large T-antigen); hFB, human fibroblasts; IRES, internal ribosomal entry site; JUN, ju-nana (17) oncogene; KRN1, keratin-associated protein 1; LUC, luciferase; MARCKS, myristoylated alanine-rich C-kinase substrate; MAX, Myc-associated factor X; MC29, avian myelocytomatosis virus 29; MH2, avian carcinoma virus MH2; MYC, avian myelocytomatosis viral oncogene homolog; Myr-NT, myristoylated BASP1 amino-terminal peptide; NK24, avian retrovirus NK24; PKC, protein kinase C; QEF, quail embryo fibroblasts; RAF, rapidly accelerated fibrosarcoma oncogene; RCAS, replication-competent avian sarcoma leukosis virus vector; RSV, Rous sarcoma virus; SRC, sarc (sarcoma) oncogene; TFP, trifluoperazine; TMX, tamoxifen; TUBA, a-tubulin; W-7, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride; WT1, Wilms' tumor 1 protein.
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