RegulationoftranscriptionalactivitybyPML

The PML nuclear bodies are ring-shaped nuclear substructures associated with the regulation of transcription, transformation, cell growth, and apoptosis and are characterized by the presence of the protein PML. The activities of PML as a tumor suppressor and apoptosis inducing factor are exerted through the numerous proteins it interacts with in the PML-nuclear bodies including the tumor suppressor p53. DNA damage induced activation of p53-dependent apoptosis requires PML. PML acts as a coactivator for p53 and increases acetylation of p53 by the transcriptional coactivator CBP. This acetylation of p53 is reversed by the deacetylase SirT1, the human homolog of the yeast gene Sir2, and this deacetylation opposes the transcriptional activation of p53. The tumor suppressor Rb also interacts with the PML nuclear body, increasing transcriptional repression of genes involved in cell cycle progression, suggesting that PML may affect cellular transformation through more than one mechanism. PML interacts directly with Ubc9, which modifies PML through the attachment of the ubiquitin-like peptide Sumo-1 (see SUMO pathway). Sumo-1 modification of PML is not necessary for the nuclear bodies to form, but may affect the recruitment of proteins that interact with PML. PML is involved in non-p53 mediated apoptotic pathways, such as DAXX-mediated apoptosis induced by Fas and TNF and regulates the transcriptional repressor activity of Daxx. The sequestration of Daxx by the PML nuclear bodies relieves the repression of other transcription factors like Pax3 by Daxx. Tumor suppression by PML may in general involve the formation of specific regulatory transcription complexes, including those with DAXX, p53 and CBP.Factors that affect the assembly of PML into the PML nuclear bodies affect the proliferation and transformation of cells. Viral early proteins can interact with PML to disrupt the nuclear bodies, allowing increased proliferation of cells and reduced apoptosis, good conditions for DNA virus infection. Another factor that disrupts the formation of PML nuclear bodies is a translocation between the PML and RAR-alpha genes found in acute promyelocytic leukemia (APL) patients. Binding of retinoic acid to the RAR-alpha steroid hormone receptor activates transcription of retinoic-acid responsive genes. The translocation found in APL patients creates two chimeric proteins, RARalpha-PML and PML-RARalpha. Retinoic acid given to APL patients causes the reappearance of nuclear bodies, and the reversal of cellular transformation, effecting a cure for these patients.

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