Background: Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of a severe and fatal lymphoproliferative disease of mainly CD4 + T cell origin, adult T cell leukemia, which develops after prolonged viral persistence. Transformation of infected cells involves HTLV-1's oncoprotein Tax, which perturbs cell cycle regulation and modulates cellular gene expression. The latter function is also a hallmark of microRNAs, a rather new layer in the regulation of gene expression. Affecting e.g. proliferation, microRNAs constitute a potential target for viral interference on the way to persistence and transformation. Hence, we explored the interconnections between HTLV-1 and cellular microRNAs.

The E1B-55K and E4orf6 proteins of adenovirus type 5 are involved in viral mRNA export. Here we demonstrate that adenovirus infection does not inhibit the function of the E1B-55K nuclear export signal and that E1B-55K also shuttles in infected cells. Even during virus infection, E1B-55K was exported by the leptomycin B-sensitive CRM1 pathway, whereas E4orf6 transport appeared to be mediated by an alternative mechanism. Our results strengthen the potential role of E1B-55K as the "driving force" for adenoviral late mRNA export.

IntroductionThe human T cell leukemia virus type 1 (HTLV-1) infection is causally linked with the development of a severe and fatal lymphoproliferative disorder of CD4 ϩ T cells, the adult T cell leukemia (ATL), and of the neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). [1][2][3][4] Both diseases develop only after prolonged viral persistence. The HTLV-1 infection seems to stimulate growth and survival of the T-lymphocytes in carriers, since they expand to detectable clones, which can persist over many years even in nonleukemic individuals. 5,6 This notion is corroborated by the virus's capacity to stimulate permanent T-lymphocyte growth in vitro, resulting in T-cell immortalization. Hence, it is highly probable that viral gene functions are not only involved in immortalization of T-cell cultures, but also cause the clonal expansion of patient lymphocytes. Such growth-stimulating functions provide means to replicate the (pro-) viral genome without producing virus particles.Being a prototypic delta-retrovirus, HTLV-1 encodes the regulatory nonstructural proteins Tax and Rex, which are essential for viral replication, 7 and the accessory proteins p12, p30, and p13. While Rex acts at a posttranscriptional level 8,9 to control the expression of the structural proteins, Tax strongly enhances viral gene expression by transactivating the HTLV-1 long-terminalrepeat promoter. 10 Although the accessory proteins are important for viral infectivity and replication by influencing cellular signaling and gene expression, [11][12][13][14][15][16] p12, p13, and p30 are dispensable for lymphocyte immortalization. 17,18 Biochemically, Tax can stimulate transcription by affecting various pathways. Nuclear factor-B (NF-B) is activated by binding and stimulating IKK␥, a component of the inhibitor of kappa B kinase. 19 Transactivation of various cellular promoters is mediated by binding to the transcriptional activators CREB and SRF, and to the coactivators p300/CBP. 10,20 Tax also induces activator protein-1 (AP-1), a transcription factor complex composed of members of the Fos/Jun family, 21,22 and stimulates transcription via nuclear factor of activated T-cell (NF-AT) elements. [23][24][25] Tax confers the transforming properties on the virus. It is capable of immortalizing T cells 26,27 and is leukemogenic in transgenic mice. 28 It interferes with normal cell-cycle control by dysregulating control checkpoints. 29 In particular, Tax is capable of stimulating the G 1 phase by binding to and activating cyclindependent kinase holoenzymes; it also inhibits DNA repair and induces aneuploidy. [30][31][32][33][34][35] Importantly, it interferes with tumor suppressor functions; for instance, it inactivates p53. 36,37 Moreover, Tax can stimulate or repress the expression of cellular proteins involved in cell survival and proliferation. Among those are proto-oncogenes (c-FOS, EGR1), cytokines, and cytokine receptors, 20,25,38 as well as cell-cycle regulators (p21 WAF1/CIP1 ). Taxmediated modulati...

Nucleo-cytoplasmic transport of proteins is mediated by nuclear export signals, identified in various proteins executing heterologous biological functions. However, the molecular mechanism underlying the orchestration of export is only poorly understood. Using microinjection of defined recombinant export substrates, we now demonstrate that leucine-rich nuclear export signals varied dramatically in determining the kinetics of export in vivo. Thus, nuclear export signals could be kinetically classified which correlated with their affinities for CRM1-containing export complexes in vitro. Strikingly, cotransfection experiments revealed that proteins containing a fast nuclear export signal inhibited export and the biological activity of proteins harboring a slower nuclear export signal in vivo. The affinity for export complexes seems therefore predominantly controlled by the nuclear export signal itself, even in the context of the complete protein in vivo. Overexpression of FG-rich repeats of nucleoporins affected a medium nuclear export signal containing protein to the same extent as a fast nuclear export signal containing protein, indicating that nucleoporins appear not to contribute significantly to nuclear export signal-specific export regulation. Our results imply a novel mode for controlling the biological activity of shuttle proteins already by the composition of the nuclear export signal itself.