RESUMEN
p53 binding protein 1 (53BP1) is a putative DNA damage sensor that accumulates at sites of double-strand breaks (DSBs) in a manner dependent on histone H2AX. Here we show that the loss of one or both copies of 53BP1 greatly accelerates lymphomagenesis in a p53-null background, suggesting that 53BP1 and p53 cooperate in tumor suppression. A subset of 53BP1-/- p53-/- lymphomas, like those in H2AX-/- p53-/- mice, were diploid and harbored clonal translocations involving antigen receptor loci, indicating misrepair of DSBs during V(D)J recombination as one cause of oncogenic transformation. Loss of a single 53BP1 allele compromised genomic stability and DSB repair, which could explain the susceptibility of 53BP1+/- mice to tumorigenesis. In addition to structural aberrations, there were high rates of chromosomal missegregation and accumulation of aneuploid cells in 53BP1-/- p53+/+ and 53BP1-/- p53-/- tumors as well as in primary 53BP1-/- splenocytes. We conclude that 53BP1 functions as a dosage-dependent caretaker that promotes genomic stability by a mechanism that preserves chromosome structure and number.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/fisiología , Neoplasias/genética , Fosfoproteínas/fisiología , Proteína p53 Supresora de Tumor/fisiología , Alelos , Secuencias de Aminoácidos , Animales , Sitios de Unión , Western Blotting , Células Cultivadas , Centrosoma/ultraestructura , Aberraciones Cromosómicas , Cromosomas/ultraestructura , Cruzamientos Genéticos , Reparación del ADN , Femenino , Genes Supresores de Tumor , Predisposición Genética a la Enfermedad , Hibridación Fluorescente in Situ , Cariotipificación , Linfoma/metabolismo , Masculino , Ratones , Ratones Transgénicos , Microscopía Fluorescente , Neoplasias/patología , Receptores de Antígenos/metabolismo , Recombinación Genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/citología , Factores de Tiempo , Translocación Genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53RESUMEN
The sodium-iodide symporter (NIS) is primarily a thyroid protein, providing for the accumulation of iodide for biosynthesis of thyroid hormones. Native NIS expression has made possible the use of radioactive iodide to image and treat thyroid disease successfully. The current study, using adult male beagle dogs, was carried out in preparation for a Phase I clinical trial of adenovirus-mediated NIS gene (approved symbol SLC5A5) therapy for prostate cancer. Direct intraprostatic injection of virus (Ad5/CMV/NS) was followed by iv injection of 3 mCi 123I and serial image acquisition. The dogs were then given a therapeutic dose of 131I (116 mCi/m2) and observed for 7 days. SPECT/CT fusion imaging revealed clear images of the NIS-transduced prostates. Dosimetry calculations revealed an average absorbed dose to the prostate of 23 +/- 42 cGy/mCi 131I, with acceptably low radiation doses to other organs. This study demonstrated the successful introduction of localized NIS expression in the prostate gland of dogs, with no vector-related toxicity observed. None of the animals experienced any surgical complications, and serum chemistry panels showed no significant change following therapy. The results presented provide further evidence of the safety and efficacy of NIS as a therapeutic gene and support translation of this work into the clinical setting.