The p53 pathway is critical for tumor suppression, as the majority of human cancer has a faulty p53. Here, we identified RNPC1, a p53 target and a RNA-binding protein, as a critical regulator of p53 translation. We showed that ectopic expression of RNPC1 inhibited, whereas knockdown of RNPC1 increased, p53 translation under normal and stress conditions. We also showed that RNPC1 prevented cap-binding protein eIF4E from binding p53 mRNA via its C-terminal domain for physical interaction with eIF4E, and its N-terminal domain for binding p53 mRNA. Consistent with this, we found that RNPC1 directly binds to p53 59 and 39untranslated regions (UTRs). Importantly, we showed that RNPC1 inhibits ectopic expression of p53 in a dose-dependent manner via p53 59 or 39 UTR. Moreover, we showed that loss of RNPC1 in mouse embryonic fibroblasts increased the level of p53 protein, leading to enhanced premature senescence in a p53-dependent manner. Finally, to explore the clinical relevance of our finding, we showed that RNPC1 was frequently overexpressed in dog lymphomas, most of which were accompanied by decreased expression of wild-type p53. Together, we identified a novel p53-RNPC1 autoregulatory loop, and our findings suggest that RNPC1 plays a role in tumorigenesis by repressing p53 translation.

Background: Histiocytic sarcoma is an aggressive neoplasm of dendritic cells that carries a grave prognosis. The efficacy of chemotherapy against this disease is unknown. The purpose of this study was to determine the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in dogs with incompletely resected or metastatic histiocytic sarcoma, to describe the clinical characteristics of these dogs, and to identify factors affecting prognosis.Hypothesis: Our hypothesis is that CCNU has activity against canine histiocytic sarcoma and can improve survival in dogs with advanced disease.Animals: Included in analysis are dogs diagnosed with histiocytic sarcoma who had gross measurable or residual microscopic disease and who received CCNU.Methods: A multi-institutional, retrospective, single-arm cohort study was conducted. Available biopsy samples were tested with an antibody against CD18 when possible to confirm the diagnosis of histiocytic sarcoma.Results: Fifty-nine dogs were treated at 8 institutions. Twenty-three tumor specimens were confirmed to be CD18 positive. Treatment with CCNU at 60 to 90 mg/m 2 resulted in an overall response rate of 46% in the 56 dogs with gross measurable disease. All 3 dogs with minimal residual disease experienced tumor relapse but lived 433 days or more after starting CCNU. The median survival of all 59 dogs was 106 days. Thrombocytopenia (,100,000 platelets/mL) and hypoalbuminemia were found to be negatively associated with prognosis and were predictive of ,1 month survival.Conclusions and Clinical Importance: Results suggest that CCNU is active against canine histiocytic sarcoma and may be useful in the treatment of dogs without negative prognostic factors.

In dogs, many previously diagnosed GILMSs should be reclassified as GISTs on the basis of results of immunohistochemical staining. The biological behavior of these tumors appears to be different.

Background: This study investigates the frequency, location, and clinical findings associated with 177 secondary brain tumors in dogs.Hypothesis: Secondary intracranial neoplasia is more common than primary intracranial neoplasia in dogs during the time period studied, and hemangiosarcoma (HSA) is the most common secondary intracranial tumor.Animals: One hundred and seventy-seven client-owned dogs presented to the Matthew J. Ryan Veterinary Hospital between 1986 and 2003.Methods: Medical records were searched for a diagnosis of intracranial neoplasia in dogs who underwent complete postmortem examination. Of these dogs, those with a diagnosis of primary intracranial neoplasia were excluded.Results: Of the 177 secondary brain tumors, 51 (29%) were HSAs, 44 (25%) were pituitary tumors, 21 (12%) were lymphosarcomas, and 21 (12%) were metastatic carcinomas. The average age at diagnosis was 9.6 AE 3.0 years. Most tumors were located in the cerebrum, and a mentation change was the most common presenting clinical sign. On postmortem examination, the same tumor that was in the brain was also present in the lung in 84 cases (47%), in the kidney in 62 cases (35%), and in the heart in 55 cases (31%).Conclusions and Clinical Importance: Secondary intracranial neoplasia in dogs was more common than primary intracranial neoplasia during the time period studied. Many of these dogs had related disease in other body systems that was apparent on diagnostic tests such as thoracic radiography.