GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis

The primary role of the Hdm2/Mdm2 oncoprotein is to regulate the levels and activity of the transcription factor p53. Hdm2 synthesis is itself tightly controlled and, as demonstrated by a recently described SNP (SNP309) in the hdm2-P2 promoter, minor variations in Hdm2 expression have phenotypic consequences on radiation sensitivity and cancer predisposition. To further define mechanisms regulating Hdm2 expression, we have investigated the effects of the GC-selective DNA-binding drug, Mithramycin A (MA) on hdm2 mRNA transcription, trafficking, and translation. Firstly we show that the constitutive hdm2-P1 promoter is inhibited by MA. We define, for the first time, the minimal sequence elements that are required for P1-promoter activity and identify those which confer MA sensitivity. Secondly, MA induces p53-dependent transcription from the hdm2-P2 promoter. Thirdly, and critically, MA also inhibits Hdm2 synthesis at the post-transcriptional level, with negative effects on hdm2 mRNA nuclear export and translation. This study highlights the complex interplay between the pathways that regulate Hdm2 protein synthesis in cancer cells, and furthermore emphasizes the export of hdm2 mRNA from the nucleus to the cytoplasm as a key point of control in this process.<br/><br/

What\u27s Wrong with Harmless Theories of Punishment

We maintain that conventional punishment theories obscure what is virtually always at the heart of punishment policy debates: harm. Namely, punishment policy disputes reflect contested views about what the harms inflicted by crime are as an empirical matter, and whether these harms ought to be acknowledged by the criminal justice regime as a normative matter. We argue that in order to know who, what, and how much to punish, one must take a position about what the harms of crime actually are. However, conventional punishment theories are mute on this question. When they supply an answer, it is because they have relied on a source outside the boundaries of their own theory to tell us why one crime is worse than another. We contend that discarding harmless theories of punishment, and instead focusing directly on competing views about the harms of crime, would clarify policy debates and open up possibilities for creative, pluralistic solutions to criminal justice problems. In addition to specifying in some detail what the harms of crime are, we offer two examples of how specific punishment policy debates would look different if they focused on harms instead of punishment theories. We also offer an illustration of a punishment policy originally motivated not by punishment theory but by a desire to explicitly address the multiple and particular harms of crime: restorative justice

What\u27s Wrong with Harmless Theories of Punishment

We maintain that conventional punishment theories obscure what is virtually always at the heart of punishment policy debates: harm. Namely, punishment policy disputes reflect contested views about what the harms inflicted by crime are as an empirical matter, and whether these harms ought to be acknowledged by the criminal justice regime as a normative matter. We argue that in order to know who, what, and how much to punish, one must take a position about what the harms of crime actually are. However, conventional punishment theories are mute on this question. When they supply an answer, it is because they have relied on a source outside the boundaries of their own theory to tell us why one crime is worse than another. We contend that discarding harmless theories of punishment, and instead focusing directly on competing views about the harms of crime, would clarify policy debates and open up possibilities for creative, pluralistic solutions to criminal justice problems. In addition to specifying in some detail what the harms of crime are, we offer two examples of how specific punishment policy debates would look different if they focused on harms instead of punishment theories. We also offer an illustration of a punishment policy originally motivated not by punishment theory but by a desire to explicitly address the multiple and particular harms of crime: restorative justice