Imre Västrik

c-Myc induces cellular susceptibility to the cytotoxic action of TNF-alpha.

Tumor necrosis factor‐alpha (TNF) is a multifunctional cytokine which is cytotoxic for some tumor cells and transformed cells. The molecular mechanisms which render transformed and tumor cells sensitive to the cytotoxic action of TNF are unclear. We show here that an increased expression of the c‐Myc oncoprotein strongly increases cellular sensitivity to TNF cytotoxicity. In Rat1A fibroblasts, which are resistant to TNF, the addition of TNF with a concomitant activation of a hormone‐inducible c‐Myc‐estrogen receptor chimera (MycER) resulted in apoptotic cell death. Similarly, c‐Myc overexpression enhanced the sensitivity of NIH3T3 fibroblasts to TNF‐induced death. The c‐Myc and TNF‐induced apoptosis was inhibited by ectopic expression of the Bcl2 oncoprotein and by the free oxygen radical scavenging enzyme Mn superoxide dismutase. Furthermore, in highly TNF‐sensitive fibrosarcoma cells, antisense c‐myc oligodeoxynucleotides caused a specific inhibition of TNF cytotoxicity. Our results suggest that the deregulation of c‐Myc, which is common in human tumors and tumor cell lines is one reason why these cells are TNF sensitive.

Alternative Forms of Max as Enhancers or Suppressors of Myc-Ras Cotransformation

Max is a basic-helix-loop-helix-Ieucine zipper protein capable of forming sequence-specific DNA binding complexes with Myc proteins. An alternatively spliced messenger RNA has been identified that encodes a form of Max truncated at the COOH-terminus. This ΔMax protein retained the ability to bind to the CACGTG motif in a complex with c-Myc but lacks the nuclear localization signal and the putative regulatory domain of Max. When tested in a myc-ras cotransformation assay in rat embryo fibroblasts, Max suppressed, whereas ΔMax enhanced, transformation. Thus, the maxgene may encode both a negative and a positive regulator of c-Myc function.

Bmx tyrosine kinase is specifically expressed in the endocardium and the endothelium of large arteries.

BACKGROUND The growth and differentiation of endothelial cells are regulated by signal transduction through tyrosine protein kinases. Recently, a novel cytoplasmic tyrosine kinase gene, Bmx (Bone Marrow tyrosine kinase gene in chromosome X), was identified in human bone marrow RNA and found to be expressed predominantly in myeloid hematopoietic cell lineages. Our preliminary analyses indicated that the Bmx gene was also highly expressed in human heart. METHODS AND RESULTS Mouse Bmx cDNA was isolated, sequenced, and found to encode a polypeptide approximately 91% identical to the human Bmx tyrosine kinase. Northern blotting and in situ hybridization of tissue sections indicated that Bmx mRNA is specifically expressed in the endocardium of the developing heart as well as in the endocardium of the left ventricle and in the endothelium of large arteries in adult mice. A weak signal was seen also in coronary arterial endothelium. CONCLUSIONS Bmx shows a unique specificity of expression among tyrosine kinase genes and may be involved in signal transduction in endocardial and arterial endothelial cells. The results suggest that specific signal transduction mechanisms are present in such endothelia.

Delivering ICT infrastructure for biomedical research

This paper describes an implementation of the Infrastructure-as-a-Service (IaaS) concept for scientific computing and seven service pilot implementations with requirements from biomedical use cases at the CSC - IT Center for Science. The key service design requirements were enabling the use of any scientific software environment the use cases needed to succeed, and delivering the distributed infrastructure ICT resources seamlessly with the local ICT resources for the scientist users. The service concept targets the IT administrators at research organisations and delivers virtualised compute cluster and storage capacity via private network solutions. The virtualised resources can become part of the local cluster as virtual nodes and they can share the same file system as the physical nodes assuming the network performance is sufficient. Extension of the local resources can then be made transparent to enable an easy infrastructure uptake to the scientist end-users. Based on 20 months of service piloting most of the biomedical organisations express a sustained and growing need for the distributed compute and storage resources delivered with the IaaS. We conclude that a successful implementation of the IaaS can improve access and reduce the effort to run expensive ICT infrastructure needed for biomedical research.

myc Amplification: regulation of Myc function

The myc oncogenes have been implicated in the control of cell proliferation in both normal and neoplastic cells. There is increasing evidence that Myc proteins function as transcriptional regulators of other genes apparently involved in the control of cell proliferation. The effects of Myc on both gene expression and cell growth are differentially regulated by the recently described Max and delta Max proteins that can either cooperate or compete with Myc for sequence-specific DNA binding.