Roles for APIS and the 20S proteasome in adenovirus E1A-dependent transcription

We have determined distinct roles for different proteasome complexes in adenovirus (Ad) E1A-dependent transcription. We show that the 19S ATPase, S8, as a component of 19S ATPase proteins independent of 20S (APIS), binds specifically to the E1A transactivation domain, conserved region 3 (CR3). Recruitment of APIS to CR3 enhances the ability of E1A to stimulate transcription from viral early gene promoters during Ad infection of human cells. The ability of CR3 to stimulate transcription in yeast is similarly dependent on the functional integrity of yeast APIS components, Sug1 and Sug2. The 20S proteasome is also recruited to CR3 independently of APIS and the 26S proteasome. Chromatin immunoprecipitation reveals that E1A, S8 and the 20S proteasome are recruited to both Ad early region gene promoters and early region gene sequences during Ad infection, suggesting their requirement in both transcriptional initiation and elongation. We also demonstrate that E1A CR3 transactivation and degradation sequences functionally overlap and that proteasome inhibitors repress E1A transcription. Taken together, these data demonstrate distinct roles for APIS and the 20S proteasome in E1A-dependent transactivation

Inflammatory Microenvironment Modulation of Alternative Splicing in Cancer: A Way to Adapt

ReviewThe relationship between inflammation and cancer has been long recognized by the medical and scientific community. In the last decades, it has returned to the forefront of clinical oncology since a wealth of knowledge has been gathered about the cells, cytokines and physiological processes that are central to both inflammation and cancer. It is now robustly established that chronic inflammation can induce certain cancers but also that solid tumors, in turn, can initiate and perpetuate local inflammatory processes that foster tumor growth and dissemination. Inflammation is the hallmark of the innate immune response to tissue damage or infection, but also mediates the activation, expansion and recruitment to the tissues of cells and antibodies of the adaptive immune system. The functional integration of both components of the immune response is crucial to identify and subdue tumor development, progression and dissemination. When this tight control goes awry, altered cells can avoid the immune surveillance and even subvert the innate immunity to promote their full oncogenic transformation. In this chapter, we make a general overview of the most recent data linking the inflammatory process to cancer. We start with the overall inflammatory cues and processes that influence the relationship between tumor and the microenvironment that surrounds it and follow the ever-increasing complexity of processes that end up producing subtle changes in the splicing of certain genes to ascertain survival advantage to cancer cells.info:eu-repo/semantics/publishedVersio

The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma

Hypoxia is an imbalance between oxygen supply and demand, which deprives cells or tissues of sufficient oxygen. It is well-established that hypoxia triggers adaptive responses, which contribute to short- and long-term pathologies such as inflammation, cardiovascular disease and cancer. Induced by both microenvironmental hypoxia and genetic mutations, the elevated expression of the hypoxia-inducible transcription factor-1 (HIF-1) and HIF-2 is a key feature of many human cancers and has been shown to promote cellular processes, which facilitate tumor progression. In this review, we discuss the emerging role of hypoxia and the HIFs in the pathogenesis of multiple myeloma (MM), an incurable hematological malignancy of BM PCs, which reside within the hypoxic BM microenvironment. The need for current and future therapeutic interventions to target HIF-1 and HIF-2 in myeloma will also be discussed.SK Martin, P Diamond, S Gronthos, DJ Peet and ACW Zannettin