Mdm2 RING mutation enhances p53 transcriptional activity and p53-p300 interaction.

The p53 transcription factor and tumor suppressor is regulated primarily by the E3 ubiquitin ligase Mdm2, which ubiquitinates p53 to target it for proteasomal degradation. Aside from its ubiquitin ligase function, Mdm2 has been believed to be capable of suppressing p53's transcriptional activity by binding with and masking the transactivation domain of p53. The ability of Mdm2 to restrain p53 activity by binding alone, without ubiquitination, was challenged by a 2007 study using a knockin mouse harboring a single cysteine-to-alanine point mutation (C462A) in Mdm2's RING domain.

Regulation of the p53 tumor suppressor pathway: the problems and promises of studying Mdm2's E3 ligase function.

Mdm2 is a major negative regulator of the tumor suppressor p53 and has long been thought to inhibit p53 in two ways: by ubiquitinating p53 to signal for its degradation, and by binding to p53, masking its transactivation domain. Mdm2 is also believed to control its own levels by autoubiquitination. Despite the widespread acceptance of these hypotheses, the supporting data were drawn primarily from in vitro and ectopic expression studies, which have not always been corroborated when tested in the more physiologically relevant setting of a knock-in or knock-out mouse model.

ARF in the mitochondria: the last frontier?

The tumor suppressor ARF carries out different functions in different cellular compartments. In the nucleus, ARF interacts physically and functionally with Mdm2 to inhibit cell cycle progression through activation of p53. In the nucleolus, ARF interacts with B23/NPM to inhibit ribosomal biogenesis through control of rRNA processing.

Unlocking the Mdm2-p53 loop: ubiquitin is the key.

Mdm2 has been thought to regulate the tumor suppressor p53 in two ways: by masking p53's access to transcriptional machinery, and by ubiquitinating p53, targeting it for proteasomal degradation. This dogma was recently challenged by data generated from knockin mice in which Mdm2's RING E3 ubiquitin ligase activity was abrogated by a single point mutation. The RING mutant Mdm2 is fully capable of binding with p53, yet cannot suppress p53 activity, suggesting that Mdm2 cannot block p53 by binding alone, without ubiquitination.

Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation.

It is believed that Mdm2 suppresses p53 in two ways: transcriptional inhibition by direct binding, and degradation via its E3 ligase activity. To study these functions physiologically, we generated mice bearing a single-residue substitution (C462A) abolishing the E3 function without affecting p53 binding. Unexpectedly, homozygous mutant mice died before E7.

The human protein kinase C gamma gene (PRKCG) as a susceptibility locus for behavioral disinhibition.

This study explores the association between a highly heritable behavioral disinhibition phenotype and the protein kinase C gamma (PRKCG) gene in an ethnically diverse youth sample from Colorado, USA. The rationale for this study was based on the impulsive behavior and increased ethanol consumption observed in the protein kinase C gamma (PKC-gamma)-deficient mouse model. Two composite behavioral disinhibition phenotypes and their component behavioral scores [conduct disorder, attention-deficit hyperactivity disorder (ADHD), substance experimentation (SUB) and novelty-seeking] were examined for association with five independent PRKCG single nucleotide polymorphisms (SNPs).

Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine.

Nicotine addiction and alcohol dependence are highly comorbid disorders that are likely to share overlapping genetic components. We have examined two neuronal nicotinic receptor subunit genes (CHRNA4 and CHRNB2) for possible associations with nicotine and alcohol phenotypes, including measures of frequency of use and measures of initial subjective response in the period shortly after first using the drugs. The subjects were 1,068 ethnically diverse young adults participating in ongoing longitudinal studies of adolescent drug behaviors at the University of Colorado, representing both clinical and community samples.