Oncogenic c-Myc-induced lymphomagenesis is inhibited non-redundantly by the p19Arf-Mdm2-p53 and RP-Mdm2-p53 pathways.

The multifaceted oncogene c-Myc plays important roles in the development and progression of human cancer. Recent in vitro and in vivo studies have shown that the p19Arf-Mdm2-p53 and the ribosomal protein (RP)-Mdm2-p53 pathways are both essential in preventing oncogenic c-Myc-induced tumorigenesis. Disruption of each pathway individually by p19Arf deletion or by Mdm2(C305F) mutation, which disrupts RP-Mdm2 binding, accelerates Eµ-myc transgene-induced pre-B/B-cell lymphoma in mice at seemingly similar paces with median survival around 10 and 11 weeks, respectively, compared to 20 weeks for Eµ-myc transgenic mice. Because p19Arf can inhibit ribosomal biogenesis through its interaction with nucleophosmin (NPM/B23), RNA helicase DDX5 and RNA polymerase I transcription termination factor (TTF-I), it has been speculated that the p19Arf-Mdm2-p53 and the RP-Mdm2-p53 pathways might be a single p19Arf-RP-Mdm2-p53 pathway, in which p19Arf activates p53 by inhibiting RP biosynthesis; thus, p19Arf deletion or Mdm2(C305F) mutation would result in similar consequences. Here, we generated mice with concurrent p19Arf deletion and Mdm2(C305F) mutation and investigated the compound mice for tumorigenesis in the absence and the presence of oncogenic c-Myc overexpression. In the absence of Eµ-myc transgene, the Mdm2(C305F) mutation did not elicit spontaneous tumors in mice, nor did it accelerate spontaneous tumors in mice with p19Arf deletion. In the presence of Eµ-myc transgene, however, Mdm2(C305F) mutation significantly accelerated p19Arf deletion-induced lymphomagenesis and promoted rapid metastasis. We found that when p19Arf-Mdm2-p53 and RP-Mdm2-p53 pathways are independently disrupted, oncogenic c-Myc-induced p53 stabilization and activation is only partially attenuated. When both pathways are concurrently disrupted, however, c-Myc-induced p53 stabilization and activation are essentially obliterated. Thus, the p19Arf-Mdm2-p53 and the RP-Mdm2-p53 are non-redundant pathways possessing similar capabilities to activate p53 upon c-Myc overexpression.

Topography of efferent vagal innervation of the rat gastrointestinal tract.

The gastrointestinal territories innervated by the gastric, celiac, and hepatic abdominal vagi were identified in rats with selective branch vagotomies by means of 1) anterograde tracing with the carbocyanine dye DiI injected into the dorsal motor nucleus and 2) measurement of cervical vagal stimulation-induced motility responses throughout the gut axis. Presence of DiI-labeled vagal terminals in the myenteric plexus and evoked motility responses were well correlated across the sampled gastrointestinal (GI) sites. In animals with only the two gastric branches intact, the entire stomach and the most proximal duodenum showed significant motility responses and were densely innervated, having DiI-labeled vagal terminals in almost every ganglion. The hepatic branch was found to primarily innervate the duodenum, with minor projections to the distal antral stomach and the intestines. The two celiac branches were found to almost exclusively innervate the jejunum, ileum, cecum and entire colon, and, together with the other vagal branches, the duodenum. Therefore, while there is some degree of specific innervation by the abdominal vagal branches of the oral-to-anal gut axis, which could be called "viscerotopic," the considerably overlapping innervation of the duodenum does not satisfy a viscerotopy criterion and needs further functional analysis.

DRL performance, extinction, and secondary reinforcement: role of appetitive value of food in mice with septal lesions.

Normal mice and mice with septal lesions were trained on a differential-reinforcement-for-low-rates-of-responding (DRL 8-sec) schedule for the reinforcement varying in incentive value. Dilution of diet increased the number of reinforcements received by mice with septal lesions. In Experiments 2 and 3 the effects of septal lesions on resistance to extinction and continuous reinforcement training and the strength of secondary reinforcement were investigated. Changes in reinforcement value modified the septal lesion effects in both cases. All three experiments demonstrated the alteration of the septal lesion effect through a change in the appetitive value of the reinforcement. The results suggest that one of the mechanisms by which septal lesions impair DRL performance is an enhancement of reinforcing properties of food.