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Tumor suppressor p53 is essential for checkpoint control in response to a variety of genotoxic stresses. DNA damage leads to phosphorylation on the Ser/Thr-Pro motifs of p53, which facilitates interaction with Pin1, a pSer/pThr-Pro-specific peptidyl prolyl isomerase. Pin1 is required for the timely activation of p53, resulting in apoptosis or cell cycle arrest. To investigate the physiological relationship between Pin1 and p53, we created Pin1−/−p53−/− mice. These p53-deficient mice spontaneously developed lymphomas, mainly of thymic origin, as well as generalized lymphoma infiltration into other organs, including the liver, kidneys and lungs. Ablation of Pin1, in addition to p53, accelerated the thymic hyperplasia, but the thymocytes in these Pin1−/−p53−/− mice did not infiltrate other organs. The thymocytes in 12-week-old Pin1−/−p53−/− mice were CD4−CD8− (double negative) and had significantly higher levels of the intracellular form of Notch1 (NIC) than the thymocytes of p53−/− or wild-type mice. Presenilin-1, a cleavage enzyme for NIC generation from full-length Notch1 was increased in the thymocytes of Pin1−/−p53−/− mice. Pin1 depletion also inhibited the degradation of NIC by proteasomes. These results suggest that both Pin1 and p53 control the normal proliferation and differentiation of thymocytes by regulating the NIC level.Oncogene (2007) 26, 3835–3845. doi:10.1038/sj.onc.1210153; published online 11 December 2006 [ABSTRACT FROM AUTHOR]

Objective and Design: Ca2+ signaling is critical for mast cell activation by antigen stimulation, and we previously described that the signaling can be mimicked by Ca2+-ATPase inhibitors. We therefore investigated the effect of the Ca2+-ATPase inhibitor and antigen stimulation on the gene expression profiles of RBL-2H3 mast cells.¶ Material: A Ca2+-ATPase inhibitor, 2,5-di( tert-butyl)-1,4-hydroquinone (DTBHQ), an antigen (dinitrophenylated BSA), a high-density oligonucleotide microarray (Affymetrix GeneChip) technique, and a well-characterized rat mast cell line RBL-2H3 were used.¶ Treatment: RBL-2H3 cells were activated for 3 h with 10 μM DTBHQ, which increases cytosolic Ca2+ concentration, or 10 μmg/ml antigen, which cross-links IgE receptors, and the mRNA expression profiles (8,799 genes) were analyzed with GeneChip arrays (n = 3).¶ Methods: Expression levels were measured by GeneChip, and the differences were tested by Welch's t-test and P-values less than 0.05 were considered statistically significant. Values are expressed as means ±SEM.¶ Results: The genes, including MCP-1, GADD45, Relaxin H1, CSF-1, c-jun-oncogene, Pyk-2, NKR-P2 and CREM, were significantly up-regulated by both DTBHQ and antigen stimuli, whereas the genes including interleukin (IL)-3, IL-4, IL-9, IL-13, GADD153, butyrate response factor, and Fas ligand, were up-regulated by DTBHQ alone. On the other hand, the expression of several genes, including GATA-1, were down-regulated by DTBHQ stimulation.¶ Conclusions: These results suggest 1) that DTBHQ seems to induce proinflammatory responses by stimulating the production of several cytokines through the expression of several transcription factors, 2) that the changes in gene expression profile induced by DTBHQ and by IgE receptor cross-linking in mast cells were almost the same, but many more stress-inducible genes like GADD153 were up-regulated by the former. [ABSTRACT FROM AUTHOR]