The c-myc proto-oncogene encodes a ubiquitous transcription factor involved in the control of cell growth and implicated in inducing tumorigenesis. Understanding the function of c-Myc and its role in cancer depends upon the identification of c-Myc target genes. Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity, and chromosomal instability. The NBS gene product, NBS1 (p95 or nibrin), is a part of the hMre11 complex, a central player associated with double-strand break (DSB) repair. NBS1 contains domains characteristic for proteins involved in DNA repair, recombination, and replication. Here we show that c-Myc directly activates NBS1. c-Myc-mediated induction of NBS1 gene transcription occurs in different tissues, is independent of cell proliferation, and is mediated by a c-Myc binding site in the intron 1 region of NBS1 gene. Overexpression of NBS1 in Rat1a cells increased cell proliferation. These results indicate that NBS1 is a direct transcriptional target of c-Myc and links the function of c-Myc to the regulation of DNA DSB repair pathway operating during DNA replication.The c-myc proto-oncogene codes for a nuclear phosphoprotein ubiquitously expressed in somatic cells (1,2). Alterations of the c-myc locus, caused by chromosomal translocation, amplification, retroviral insertion, or retroviral transduction, deregulate c-Myc expression and contribute to tumorigenesis in different species (1,(3)(4)(5). The c-Myc protein contains a carboxyl-terminal basic, helix-loop-helix and leucine-zipper domain, which associates with another basic, helix-loop-helix and leucine-zipper protein (MAX) 1 as heterodimers, and an amino-terminal domain necessary for transcriptional transactivation (2, 6, 7). The heterodimeric complexes c-Myc⅐MAX are capable of binding DNA at a specific site (E-box) and activate transcription of downstream target genes by recruiting protein complexes that can regulate histone acetylation and modify chromatin structure (8 -10).The precise function of the c-Myc protein, and in particular the mechanism by which it promotes cell proliferation in normal and neoplastic cells, is not known. Using a variety of approaches, including genome-wide gene expression profiling, various c-Myc target genes have been identified and have been shown to be involved in heterogeneous functions, including cell cycle control, DNA synthesis, iron metabolism, protein synthesis, apoptosis, cell adhesion, and telomere maintenance (11). In Drosophila as well as in mammalian cells, c-Myc has been shown to promote cell growth (12, 13), although it has been recently reported that c-Myc may control organ and body size by regulating cell cycle entrance and cell number rather than cell size (14). A better understanding of the precise role of c-Myc depends upon the identification of the genes that are directly targeted by its transcriptional regulation.Nijmegen breakage syndrome (NBS) is an autosomal recessive hereditary disorder characterized by microcephaly,...

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Melanoma is the most prevalent type of skin cancer with high mortality rates. This study demonstrates the in vitro and in vivo anticancer properties of chalcone flavokawain B (FKB) induced ROS-mediated apoptosis and autophagy in human melanoma (human epithelial melanoma cell line A375 and/or human skin lymph node derived melanoma cell line A2058) cells. Cell viability was calculated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the expression patterns of various apoptosis, autophagy-associated proteins were determined by Western blot methods. Annexin V was detected by flow cytometry, whereas acidic vesicular organelles (AVOs) and intracellular ROS levels were measured by fluorescence microscopy. The in vivo anticancer properties of FKB were evaluated by xenografting the A375 cells into nude mice. The results convey that FKB inhibited cell viability, B-Raf proto-oncogene, serine/threonine kinase (BRAF)/extracellular signal-regulated kinase (ERK) expression in human melanoma cells. Caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage pathway, and Bcl2 associated X (Bax)/B-cell lymphoma 2 (Bcl-2) dysregulation were involved in the execution of apoptosis. Moreover, FKB-induced autophagy was observed through increased microtubule-associated protein 1A/1B-light chain 3B (LC3-II) accumulation and AVOs formation, which was also associated with an increase in sequestosome 1 (SQSTM1/p62), decreased protein kinase B (AKT)/mammalian target of rapamycin (mTOR) expressions, and dysregulated Beclin-1/Bcl-2 levels. Autophagy inhibitors [3-methyladenine (3-MA)/chloroquine (CQ)] and LC3 silencing suppressed FKB-induced apoptosis by decreasing caspase-3 in melanoma cells. The antioxidant N-acetylcysteine (NAC) diminished FKB-induced apoptotic and autophagic cell death. However, the inhibition of apoptosis decreased FKB-induced autophagy (LC3-I/II). The in vivo study confirmed that FKB inhibited melanoma growth in A375-xenografted nude mice. This study concluded that FKB is critically associated with the execution and generation of ROS-modulated apoptotic and autophagic cell death of melanoma cells. FKB also repressed tumor growth in xenografted nude mice. Therefore, flavokawain B might be a potential anti-tumor agent in human melanoma treatment.

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