The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4؉ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30 II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30 II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30 II /Myc-TIP60 chromatin-remodeling complexes. The p30 II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30 II interact with the TIP60 HAT, and p30 II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30 II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis.

The human immunodeficiency virus type-1 (HIV-1) infects microglia, macrophages, and astrocytes in the central nervous system (CNS) and may cause severe neurological diseases, such as AIDS-related dementias or progressive encephalopathies, as a result of CNS inflammation and neurotrophin signaling defects associated with expression of viral antigens and HIV-1 replication in the brain. The HIV Tat protein can be endocytosed by surrounding uninfected cells; interacts with transcriptional coactivators/acetyltransferases,

The transcriptional coactivators, p300/CREB-binding protein-associated factor (PCAF) and hGCN5, are recruited to chromatin-remodeling complexes on enhancers of various gene promoters in response to growth factor stimulation. However, the molecular mechanisms by which surface receptor signals modulate the assembly of nuclear transcription complexes are not fully understood. Here we report that nerve growth factor receptor signaling induces nuclear translocation of PCAF and hGCN5 dependent upon the phosphorylation of Ser and Thr residues within their histone acetyltransferase domains, which requires activation of PI3K, Rsk2 pp90 , and MSK-1. Neurotrophin stimulation induces p53 K320 acetylation by PCAF and transcriptionally activates p53-responsive enhancer elements within the p21 WAF/CIP1 promoter associated with G 1 /S arrest during neuronal differentiation. Most importantly, these findings represent the first evidence for signal-dependent nuclear translocation of PCAF and hGCN5 acetyltransferases and allude to a novel mechanism for ligand/receptor modulation of nuclear chromatin-remodeling complexes in neurons.Neurotrophin receptor signaling is essential for neuronal differentiation, synapse formation and plasticity, protection against apoptosis, and neuronal injury-repair (1-10). Binding of NGF 1 to its high affinity receptor (p140 TrkA ) on surfaces of target cells activates intracellular signaling cascades that involve PI3K, Ras, mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs) and converge upon nuclear Ca 2ϩ -dependent kinases, such as ribosomal S6 kinase-2 (Rsk2 pp90 ) and mitogen-and stress-activated protein kinases-1/2 (MSK-1/2) that phosphorylate the cyclic AMP-responsive element-binding protein (CREB) on Ser 133 to activate transcription from CRE-containing gene promoters (1,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Nerve growth factor receptor signaling also transcriptionally activates p53-responsive elements within the p21 WAF/CIP1 promoter associated with G 1 /S cellular arrest and neuronal differentiation (21-23). Both CREB and p53 recruit the coactivators/ HATs, p300/CBP and PCAF, to promoters of responsive genes to facilitate chromatin remodeling (through site-specific acetylation of lysine residues within NH 2 termini of histones H3/H4) and the recruitment of basal transcription factors, TBP, TFIIB, and RNA Pol II (24 -36). Although the intracellular events that transmit NGF receptor signals to the nucleus have been widely characterized, relatively little is known regarding the mechanisms for recruitment of transcriptional coactivators/acetyltransferases (PCAF andhGCN5) to chromatin-remodeling complexes assembled on promoters of target genes in response to growth factor stimulation (24,34,(37)(38)(39)(40)(41)(42)(43)(44)).Here we demonstrate that NGF receptor signaling induces phosphorylation and HAT domain-dependent nuclear translocation of PCAF and hGCN5 acetyltransferases. Our results suggest that signal-dependent HAT trafficking may increase the complexit...

(1) have demonstrated that WRN contributes to general RNA pol II 4 -dependent transcription, although its mechanism remains unclear. Interestingly, these authors found that a 27-amino acid direct-repeat sequence strongly activated transcription in yeast two-hybrid experiments, independent of WRN 3Ј 3 5Ј DNA helicase activity (1) (Fig. 1A) suggesting that WRN interacts with cellular factors to modulate RNA pol II-dependent transcription. The WRN protein localizes to nucleoli and the nucleoplasm of transcriptionally active cells (1, 2). Moreover, Laine et al. (3) have shown that WRN stimulates topoisomerase I DNA-unwinding activity that could influence cellular transcription. The yeast WRN homologue, SGS1, also participates in DNA replication and RNA pol I-dependent transcription (4), and the WRN helicase enhances RNA pol I-dependent transcription of ribosomal RNA (5).In the present study, we have investigated whether WRN contributes to HIV-1 LTR transactivation and retroviral replication. The HIV-1 LTR contains upstream enhancer elements (e.g. NF-B and SP1) that synergize with the transactivator protein, Tat, bound to TAR-RNA, to promote retroviral gene expression in HIV-1-infected tissues, macrophages/monocytes, and CD4 ϩ T-lymphocytes (6 -17). The mechanism by which Tat/TAR-RNA complexes regulate transcription from the HIV-1 LTR involves the concerted recruitment of a plethora of cellular factors, including p300/CREB-binding protein (p300/CBP) (18 -25), [26][27][28][29][30], P-TEFb (30 -33), SET7/SET9 methyltransferases (34), SIRT1 (35), the Brm component of the SWI/SNF chromatin-remodeling com-