Tale of a multifaceted co-activator, hADA3: from embryogenesis to cancer and beyond.

Human ADA3, the evolutionarily conserved transcriptional co-activator, remains the unified part of multiple cellular functions, including regulation of nuclear receptor functions, cell proliferation, apoptosis, senescence, chromatin remodelling, genomic stability and chromosomal maintenance. The past decade has witnessed exciting findings leading to considerable expansion in research related to the biology and regulation of hADA3. Embryonic lethality in homozygous knockout Ada3 mouse signifies the importance of this gene product during early embryonic development. Moreover, the fact that it is a novel target of Human Papillomavirus E6 oncoprotein, one of the most prevalent causal agents behind cervical cancer, helps highlight some of the crucial aspects of HPV-mediated oncogenesis. These findings imply the central involvement of hADA3 in regulation of various cellular functional losses accountable for the genesis of malignancy and viral infections. Recent reports also provide evidence for post-translational modifications of hADA3 leading to its instability and contributing to the malignant phenotype of cervical cancer cells. Furthermore, its association with poor prognosis of breast cancer suggests intimate association in the pathogenesis of the disease. Here, we present the first review on hADA3 with a comprehensive outlook on the molecular and functional roles of hADA3 to provoke further interest for more elegant and intensive studies exploring assorted aspects of this protein.

Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responses.

Bruton tyrosine kinase (Btk), a non-receptor-associated tyrosine kinase of the Tec family, appears to participate in many myeloid cell functions. We show that macrophages from X-linked immunodeficient (XID) mice lacking functional Btk cannot generate efficient bursts of reactive oxygen intermediates (ROIs). The induction of apoptotic cell death by inflammatory stimuli is also enhanced in XID macrophages. Phagocytosis of bacterial particles is only marginally affected in them. In vivo, XID mice show reduced severity of inflammatory diseases in models of experimental autoimmune encephalomyelitis (EAE), dextran sulfate sodium (DSS)-induced colitis, and carrageenan-induced acute edema. Also, polymorphonuclear neutrophil granulocytes (PMNs) in XID mice show poor ROI and nitric oxide (NO) induction, along with a reduction in PMN recruitment to peritoneal inflammation. XID mice show reduction in PMN numbers in peripheral blood, and their bone marrow shows a reduction in the numbers of both monocytic and granulocytic lineages, extending to the earliest progenitor populations. Thus, Btk is likely to play a significant role at multiple points during the development and functioning of the myeloid lineages, affecting the outcome of many infectious as well as noninfectious inflammatory events in vivo.

Macrophage effector functions controlled by Bruton's tyrosine kinase are more crucial than the cytokine balance of T cell responses for microfilarial clearance.

Macrophages from X-linked immunodeficient (xid) mice lacking functional Bruton's tyrosine kinase (Btk) show poor NO induction and enhanced IL-12 induction, and contribute to delayed clearance of injected microfilaria (mf) in vivo. We now show that Btk is involved in other macrophage effector functions, such as bactericidal activity and secretion of proinflammatory cytokines (TNF-alpha, IL-1beta), but not the T cell-directed cytokine IL-12. Induction of some transcriptional regulators of the NF-kappaB family, crucial for the expression of proinflammatory cytokines, is also poor in Btk-deficient macrophages. Thus, Btk appears to be involved in signaling for inducible effector functions, but not APC functions, in macrophages. Furthermore, adoptive transfer of T cells from mf-infected xid or wild-type mice did not alter the course of mf clearance in recipients, mf clearance was unaltered in IFN-gamma-deficient mice, and improved mf clearance was seen only if greater inducibility of IL-12 was accompanied by greater NO secretion from macrophages, as seen in Ity(r) C.D2 mice as compared with congenic Ity(s) BALB/c mice. Thus, delayed mf clearance in xid mice was correlated not with the high IL-12/Th1 phenotype but with low NO induction levels. Also, xid macrophages showed poor toxicity to mf in vitro as compared with wild-type macrophages. Inhibition of NO production blocked this mf cytotoxicity, and an NF-kappaB inhibitor blocked both NO induction and mf cytotoxicity. Thus, Btk is involved in inducing many macrophage effector functions, and delayed mf clearance seen in Btk-deficient xid mice is due to poor NO induction in macrophages, resulting in compromised microfilarial toxicity.