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The viral form of the AP-1 subunit Jun sets up one aspect of transformation in chick embryo fibroblasts (CEFs). The complexity of AP-1 factors has been cut down by constructing Jun bZip mutants that can dimerize and transactivate efficiently with no more than a restricted set of partner subunits. The object was to identify programs that relate to cell transformation. A Jun mutant selective for the Fos family induced anchorage-independent growth but no growth-factor independence when introduced into CEFs. A c-Jun mutant with preference for ATF2-like proteins caused growth-factor independence but no growth in agar. Coexpressed, the mutants reestablished the combined transformation program.

Apoptin, a viral death protein derived from chicken anemia virus, displays a number of tumor-specific behaviors. In particular, apoptin is phosphorylated, translocates to the nucleus, and induces apoptosis specifically in tumor or transformed cells, whereas it is nonphosphorylated and remains primarily inactive in the cytoplasm of nontransformed normal cells. Here, we show that in normal cells apoptin can also be activated by the transient transforming signals conferred by ectopically expressed simian virus 40 (SV40) large T antigen (LT), which rapidly induces apoptin's phosphorylation, nuclear accumulation, and the ability to induce apoptosis. Further analyses with mutants of LT showed that the minimum domain capable of inducing all three of apoptin's tumor-specific properties resided in the N-terminal J domain, a sequence which is largely shared by SV40 small t antigen (st). Interestingly, the J domain in st, which lacks its own nuclear localization signal (NLS), required nuclear localization to activate apoptin. These results reveal the existence of a cellular pathway shared by conditions of transient transformation and the stable cancerous or precancerous state, and they support a model whereby a transient transforming signal confers on apoptin both the upstream activity of phosphorylation and the downstream activity of nuclear accumulation and apoptosis induction. Such a pathway may reflect a general lesion contributing to human cancers. [ABSTRACT FROM AUTHOR]

Transcription factor ATF2 regulates gene expression in response to environmental changes. Upon exposure to cellular stresses, the mitogen-activated protein- kinase (MAPK) cascades including SAPK/JNK and p38 can enhance ATF2's transactivating function through phosphorylation of Thr69 and Thr7l. However, the mechanism of ATF2 activation by growth factors that are poor activators of JNK and p38 is still elusive. Here, we show that in fibroblasts, insulin, epidermal growth factor (EGF) and serum activate ATF2 via a so far unknown two-step mechanism involving two distinct Ras effector pathways: the Raf-MEK-ERK pathway induces phosphorylation of ATF2 Thr71, whereas subsequent ATF2 Thr69 phosphorylation requires the Ral-RaIGDS-Src-p38 pathway. Cooperation between ERK and p38 was found to be essential for ATF2 activation by these mitogens; the activity of p38 and JNK/SAPK in growth factor-stimulated fibroblasts is insufficient to phosphorylate ATF2 Thr71 or Thr69 + 71 significantly by themselves, while ERK cannot dual phosphorylate ATF2 Thr69 + 71 efficiently. These results reveal a so far unknown mechanism by which distinct MAPK pathways and Ras effector pathways cooperate to activate a transcription factor. [ABSTRACT FROM AUTHOR]

Viruses can produce viral oncoproteins that drive multiple genetic alterations as the consequence of neoplastic transformation. Viral proteins encoded by onco-related viruses such as polyomavirus SV40 or Epstein-Barr virus are involved in cellular processes resulting in imbalance between proliferation and cell death, knowledge of which continues to be crucial for combating cancer. On the other hand, viruses also generate viral components that, from a cold viral protein, can become a tumor-selective killer by sensing cellular tumorigenic hallmarks. For instance, the avian virus derived apoptin protein has been proven to induce tumor-regression in various pre-clinical animal models without showing detectable side effects. In particular, apoptin-interacting protein partners such as components of the anaphase promoting complex were identified as potential anticancer drug targets. The adenovirus-derived protein E4orf4, another viral protein with tumor-specific apoptosis characteristics, has been proven to interact with the tumor-suppressor protein phosphatase 2A. This review aims to describe recent studies with representative viral elements that have contributed to our understanding of critical tumorigenic processes and have conferred an impact on the development of novel anti-cancer therapies.

Nonfunctional p53 and especially upregulation of Bcl-x(L) result in advanced disease and poor prognosis of patients suffering head and neck squamous cell carcinoma (HNSCC). Aberrancies of Bcl-x(L) and/or p53 in HNSCC lead to inability of anticancer drugs to induce apoptosis. Bcl-x(L) and/or mutated p53 inhibit the apoptotic process by preventing the mitochondrial release of cytochrome c and/or activation of execution caspases. Here, we report that expression of the avian virus-derived apoptin protein resulted in induction of apoptosis in the HNSCC-derived cell line UMSSC-14B despite the presence of nonfunctional p53. Apoptin activated the execution caspase 3 and induced the release of mitochondrial cytochrome c. Upregulation of Bcl-x(L) in UMSCC-14B cells did not interfere with the apoptin-induced apoptosis, whereas it clearly negatively affected the p53-induced one. Bcl-x(L) significantly decreased the p53-induced cytochrome c release, but not the apoptin-triggered one. Our data demonstrate that apoptin induces apoptosis independent of Bcl-x(L) and p53 and may constitute a potential therapeutic agent for treatment of HNSCC., (Copyright 2003 Wiley-Liss, Inc.)