ASPP2 stimulates the apoptotic function of the p53 family in vivo. We show here that ASPP2 −/− pups died before weaning. This postnatal lethality was significantly enhanced in p53 +/− background and both deletions are synthetic lethal. ASPP2 +/− mice developed spontaneous tumors. The tumor onset was accelerated by ␥-irradiation or in p53 +/− background. Tumors derived from ASPP2 +/− mice retained wild-type ASPP2 allele even though some of them lost p53. These provide the first genetic evidence that ASPP2 is a haploinsufficient tumor suppressor that shares overlapping function(s) with p53 in mouse development and tumor suppression. ASPP2 belongs to the evolutionarily conserved ASPP (ankyrin repeats, SH3 domain, and proline-rich region containing protein) family of proteins (Samuels-Lev et al. 2001;Bergamaschi et al. 2003;Slee and Lu, 2003). ASPP2 was previously identified as an interacting partner for a number of proteins, including p53 (Iwabuchi et al. 1994), Bcl-2 (Naumovski and Cleary 1996), RelA p65 (Yang et al. 1999), Yap (Espanel andSudol 2001), APC-2(APCL) (Nakagawa et al. 2000), APP-BP1 (Chen et al. 2003), and protein phosphatase 1 (PP1) (Helps et al. 1995). All of these proteins, with the exception of APP-BP1, interact with the C-terminal region of ASPP2. The residues involved in the interactions between ASPP2 and p53 or PP1 were identified through crystal structure studies (Gorina and Pavletich 1996;Egloff et al. 1997). ASPP2 binds to the evolutionarily conserved DNAbinding domain of p53, and all ASPP2 contact residues of p53 are mutated in human cancers (Gorina and Pavletich 1996). This suggests that ASPP2/p53 interaction might have a tumor suppression function. Consistent with this, the ASPP2/p53 interaction specifically stimulates the apoptotic function of p53 (Samuels-Lev et al. 2001) and its family members p63 and p73 (Bergamaschi et al. 2004). This is achieved through the ability of ASPP2 to enhance the DNA-binding and transactivation function of p53, p63, and p73 on promoters of Bax, PIG3, and PUMA, but not on p21 waf1 nor on mdm2. The biological significance of the interaction between ASPP2 and non-p53 family proteins remains unclear. ASPP2 does not bind to the catalytic domain of PP1, although the peptide of ASPP2 containing the PP1-binding motif (RXVF) is able to inhibit the phosphatase activity of PP1 (Egloff et al. 1997). The binding of ASPP2 to APP-BP1 prevents the apoptotic function of APP-BP1 in neuronal cells by influencing the neddylation of cullin, suggesting that ASPP2 might have an antiapoptotic function in some contexts (Chen et al. 2003). The ASPP2/p65 interaction did not have a dramatic effect on the transactivation function of p65 (Yang et al. 1999).In order to provide an in vivo model system to study the biological functions of ASPP2, we generated and characterized ASPP2-deficient mice. This revealed that ASPP2 is required during the development of the brain and heart. Also, heterozygosity of ASPP2-null allele significantly accelerated tumor development. To test the biological ...

Antibiotic C3368-A (CA) is produced by a fungus strain from a soil sample collected in Antarctica. CA markedly inhibited radiolabeled thymidine and uridine transport in mouse Ehrlich carcinoma cells, its 50% inhibitory concentration (IC50) being 4.6 and 7.7 microM, respectively. In clonogenic assay, CA displayed a synergistic effect with methotrexate (MTX), mitomycin C (MMC), 5-fluorouracil (5FU), and Adriamycin (ADR) against human oral epidermoid carcinoma KB cells. CA also markedly enhanced the inhibitory effect of 5FU and ADR on the proliferation of human hepatoma BEL-7402 cells as determined by the p-nitrophenyl-N-acetyl-beta-D-glucosaminide (NAG) enzyme-reaction assay. 5FU or ADR cytotoxicity was not augmented by CA in human fetal lung 2BS cells. In vivo, CA significantly potentiated the inhibitory effect of MMC against colon carcinoma 26 in mice. No significant augmentation of toxicity by the combination was found in treated mice. The results suggest that CA, the newly found nucleoside-transport inhibitor, may be useful in potentiation of the effect of antitumor drugs.

The bone defect repairing is still a challenge in orthopedics. As the gene engineering bones have been used in the bone repairing clinic, the scaffold construction is a critical fact to be considered. This study aims to construct optimal scaffolds using adipose tissue in the bone repair together with the gene engineering osteocytes. Rat adipose stem cells (ASC) were prepared; the cells were transduced with the OCT-4 gene carrying lentiviral vectors (OCT-4-Lv). Artificial bone defects were created in the rat femoral bone. The bone defects were filled up with adipose scaffolds and shaped by using surrounding muscles and supported with orthopedic splints. ASCs with or without transducing the OCT-4-Lv were injected into the adipose scaffolds. The rats were sacrificed 12 weeks after the surgery. After receiving the OCT-4-Lv, the expressions of OCT-4, RUNX2 and osteocalcin were detected in the ASCs. X-ray examination showed that rats received the OCT-4-Lv transduced ASCs together with the adipose pad had new bone formation in the defect area; none of the control rats showed any new bone formation in situ. The results were supported by histological assessment. Using adipose scaffold and OCT-4-modified ASC transplantation can repair bone defects.

No abstract

No abstract