MYB transcription factors are highly conserved from plants to vertebrates, indicating that their functions embrace fundamental mechanisms in the biology of cells and organisms. In humans, theMYBgene family is composed of three members:MYB,MYBL1andMYBL2, encoding the transcription factors MYB, MYBL1, and MYBL2 (also known as c-MYB, A-MYB, and B-MYB), respectively. A truncated version of MYB, the prototype member of the MYB family, was originally identified as the product of the retroviral oncogenev-myb, which causes leukaemia in birds. This led to the hypothesis that aberrant activation of vertebrate MYB could also cause cancer. Despite more than three decades have elapsed since the isolation of v-myb, only recently investigators were able to detectMYBgenes rearrangements and mutations, smoking gun evidence of the involvement ofMYBfamily members in human cancer. In this review, we will highlight studies linking the activity ofMYBfamily members to human malignancies and experimental therapeutic interventions tailored forMYB-expressing cancers.

Apolipoprotein J/clusterin is an enigmatic protein highly regulated in inflammation, apoptosis, and cancer. Despite extensive studies, its biological function has remained obscure. Here we show that apolipoprotein J inhibits neuroblastoma cell invasion. Since this function can be regulated by NF-κB, we explored the possibility that apolipoprotein J might interfere with NF-κB signaling. Ectopic apolipoprotein J expression strongly inhibited NF-κB activity in human neuroblastoma cells and murine embryonic fibroblasts by stabilizing inhibitors of NF-κB (IκBs). Steady state levels of IκB proteins are drastically reduced in mouse embryo fibroblasts after disruption of the apolipoprotein J gene. Absence of apolipoprotein J causes reduction of IκB stability, a tumor necrosis factor-dependent increase in NF-κB activity, increased transcription of the NF-κB target gene c-IAP and down-modulation of p53 protein. These results suggest that an unexpected physiological role of apolipoprotein J is to inhibit NF-κB signaling through stabilization of IκBs and that this activity may result in suppression of tumor cell motility.

Frizzled receptors are the mediators of the wnt canonical and non-canonical pathways, which play fundamental roles in cell differentiation and organism development. A large body of work indicates that dysregulation of wnt signalling is a feature of oncogenic transformation, but most of the studies published so far focus on the assessment of the consequences of aberrations of the canonical pathway in human cancer. In this review, we discuss the emerging role of the wnt non-canonical pathway regulated by frizzled receptor 6 (Fzd6) in the pathogenesis of different types of human malignancies. The function played by Fzd6 in the physiology of normal and cancer cells has been highlighted in the view that an increased knowledge of the signalling pathways upstream and downstream of this receptor could ultimately result in the identification of new targets for cancer therapy.

FIP3, isolated as a type 2 adenovirus E3–14.7-kDa interacting protein, is an essential component of the multimeric IκB-α kinase (IKK) complex and has been shown to interact with various components (Fas receptor-interacting protein, NF-κB-inducing kinase, IKKβ) of the NF-κB activation pathway. FIP3 has also been shown to repress basal and tumor necrosis factor (TNF) α-induced NF-κB activity as well as to induce cell death when overexpressed. The adenovirus E3–14.7-kDa protein (E3-14.7K) is an inhibitor of TNFα-induced cell death. In the current study, we generated deletion mutants to map the domains of FIP3, which are responsible for its various functions. The NF-κB inhibitory activity and the E3–14.7K binding domains were mapped at the carboxyl half of the FIP3 protein. We also found that the carboxyl-terminal half of FIP3 blocked TNFα-induced IκB-α phosphorylation and subsequent degradation, which suggests that the stabilization of the cytoplasmic inhibitor of NF-κB underlies the FIP3 inhibition of NF-κB activity. The amino-terminal 119 amino acids were responsible for the FIP3-IKKβ and FIP3-IKKα interaction, and the middle of the protein (amino acids 201–300) appeared to be both the FIP3 self-association domain as well as the FIP3-Fas receptor-interacting protein interaction domain. Thus, FIP3 might serve as a scaffold protein to organize the various components of the IκB-α kinase complex. Whereas the full-length protein is required for efficient cell death, the amino-terminal 200 amino acids are sufficient to cause rounding and detachment of the cells from the monolayer.

B-MYB is a ubiquitously expressed transcription factor involved in the regulation of cell survival, proliferation, and differentiation. In an attempt to isolate B-MYB-regulated genes that may explain the role of B-MYB in cellular processes, representational difference analysis was performed in neuroblastoma cell lines with different levels of B-MYB expression. One of the genes, the mRNA levels of which were enhanced in B-MYB expressing cells, was ApoJ/Clusterin(SGP-2/TRMP-2) (ApoJ/Clusterin), previously implicated in regulation of apoptosis and tumor progression. Here we show that the human ApoJ/Clusterin gene contains a Myb binding site in its 5' flanking region, which interacts with bacterially synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the ApoJ/Clusterin promoter in transient transfection assays. Endogenous ApoJ/Clusterin expression is induced in mammalian cell lines following transient transfection of a B-MYB cDNA. Blockage of secreted clusterin by a monoclonal antibody results in increased apoptosis of neuroblastoma cells exposed to the chemotherapeutic drug doxorubicin. Thus, activation of ApoJ/Clusterin by B-MYB may be an important step in the regulation of apoptosis in normal and diseased cells.