PAF1 complex component Leo1 helps recruit Drosophila Myc to promoters.

The Myc oncogene is a transcription factor with a powerful grip on cellular growth and proliferation. The physical interaction of Myc with the E-box DNA motif has been extensively characterized, but it is less clear whether this sequence-specific interaction is sufficient for Myc's binding to its transcriptional targets. Here we identify the PAF1 complex, and specifically its component Leo1, as a factor that helps recruit Myc to target genes. Since the PAF1 complex is typically associated with active genes, this interaction with Leo1 contributes to Myc targeting to open promoters.

Max-independent functions of Myc in Drosophila melanogaster.

Myc proteins are powerful proto-oncoproteins and important promoters of growth and proliferation during normal development. They are thought to exercise their effects upon binding to their partner protein Max, and their activities are largely antagonized by complexes of Max with Mnt or an Mxd family protein. Although the biological functions of Myc, Mxd and Mnt have been intensively studied, comparatively little is known about the in vivo role of Max. Here we generate Max loss-of-function and reduction-of-function mutations in Drosophila melanogaster to address the contribution of Max to Myc-dependent growth control. We find that many biological activities of Myc do not, or only partly, require the association with Max--for example, the control of endoreplication and cell competition-and that a Myc mutant that does not interact with Max retains substantial biological activity. We further show that Myc can control RNA polymerase III independently of Max, which explains some of Myc's observed biological activities. These studies show the ability of Myc to function independently of Max in vivo and thus change the current model of Max network function.

Drosophila Myc interacts with host cell factor (dHCF) to activate transcription and control growth.

The Myc proto-oncoproteins are transcription factors that recognize numerous target genes through hexameric DNA sequences called E-boxes. The mechanism by which they then activate the expression of these targets is still under debate. Here, we use an RNAi screen in Drosophila S2 cells to identify Drosophila host cell factor (dHCF) as a novel co-factor for Myc that is functionally required for the activation of a Myc-dependent reporter construct. dHCF is also essential for the full activation of endogenous Myc target genes in S2 cells, and for the ability of Myc to promote growth in vivo. Myc and dHCF physically interact, and they colocalize on common target genes. Furthermore, down-regulation of dHCF-associated histone acetyltransferase and histone methyltransferase complexes in vivo interferes with the Myc biological activities. We therefore propose that dHCF recruits such chromatin-modifying complexes and thereby contributes to the expression of Myc targets and hence to the execution of Myc biological activities.

Whole-genome analysis reveals a strong positional bias of conserved dMyc-dependent E-boxes.

Myc is a transcription factor with diverse biological effects ranging from the control of cellular proliferation and growth to the induction of apoptosis. Here we present a comprehensive analysis of the transcriptional targets of the sole Myc ortholog in Drosophila melanogaster, dMyc. We show that the genes that are down-regulated in response to dmyc inhibition are largely identical to those that are up-regulated after dMyc overexpression and that many of them play a role in growth control. The promoter regions of these targets are characterized by the presence of the E-box sequence CACGTG, a known dMyc binding site. Surprisingly, a large subgroup of (functionally related) dMyc targets contains a single E-box located within the first 100 nucleotides after the transcription start site. The relevance of this E-box and its position was confirmed by a mutational analysis of a selected dMyc target and by the observation of its evolutionary conservation in a different Drosophila species, Drosophila pseudoobscura. These observations raise the possibility that a subset of Myc targets share a distinct regulatory mechanism.

Startle reactivity in the long-term after severe accidental injury: preliminary data.

An exaggerated startle response is one of the core hyperarousal symptoms of posttraumatic stress disorder (PTSD). Heightened startle eye-blink magnitude and reduced habituation of this response in PTSD patients have been reported in several studies. However, it is unclear whether this is an enduring characteristic of individuals vulnerable for PTSD or to which degree trauma-exposed individuals who do not develop PTSD also show exaggerated startle. Thirteen accident survivors with remitted PTSD, 12 trauma controls, and 16 non-trauma controls were examined. Four measures of startle reactivity were analyzed in response to 15 bursts of white noise (95 dB, 50 ms): eye-blink magnitude, eye-blink onset latency, skin conductance response, and heart rate response. The eye-blink reflex was measured over the left musculus orbicularis oculi. Reactivity and habituation were analyzed using linear mixed models. Remitted PTSD subjects did not differ from non-trauma controls regarding any of the startle reactivity or habituation measures. Unexpectedly, trauma controls showed larger eye-blink magnitude than non-trauma controls. These results suggest that the exaggerated startle response disappears after remission from PTSD. Further, they suggest that psychologically resilient trauma survivors might show a PTSD-like pattern of exaggerated physiological startle even many years after a traumatic event.