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To investigate the effect of mutations in the p53 C-terminal domain on MDM2-mediated degradation, we introduced single and multiple point mutations into a human p53 cDNA at four putative acetylation sites (amino acid residues 372, 373, 381, and 382). Substitution of all four lysine residues by alanines (the A4 mutant) and single lysine-to-alanine substitutions were functional in sequence-specific DNA binding and transactivation; however, the A4 mutant protein was resistant to MDM2-mediated degradation, whereas the single lysine substitutions were not. Although the A4 mutant protein and the single lysine substitutions both bound MDM2 reasonably well, the single lysine substitutions underwent normal MDM2-dependent ubiquitination, whereas the A4 protein was inefficiently ubiquitinated. In addition, the A4 mutant protein was found in the cytoplasm as well as in the nucleus of a subpopulation of cells, unlike wild-type p53, which is mostly nuclear. The partially cytoplasmic distribution of A4 mutant protein was not due to a defect in nuclear import because inhibition of nuclear export by leptomycin B resulted in nuclear accumulation of the protein. Taken together, the data suggest that mutations in the putative acetylation sites of the p53 C-terminal domain interfere with ubiquitination, thereby regulating p53 degradation.

[formula: see text] The enantioselective intramolecular C-H insertion reaction of aryldiazoacetates has been explored with use of dirhodium(II) carboxylate catalysts, which incorporate N-phthaloyl- or N-benzene-fused-phthaloyl-(S)-amino acids as chiral bridging ligands. Dirhodium tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh2(S-PTTL)4, has proven to be the catalyst of choice for this process, providing exclusively cis-2-aryl-3-methoxycarbonyl-2,3-dihydobenzofurans in up to 94% ee.

The coastal belt of Karunagappally, Kerala, India, is known for high background radiation (HBR) from thorium-containing monazite sand. In coastal panchayats, median outdoor radiation levels are more than 4 mGy y-1 and, in certain locations on the coast, it is as high as 70 mGy y-1. Although HBR has been repeatedly shown to increase the frequency of chromosome aberrations in the circulating lymphocytes of exposed persons, its carcinogenic effect is still unproven. A cohort of all 385,103 residents in Karunagappally was established in the 1990's to evaluate health effects of HBR. Based on radiation level measurements, a radiation subcohort consisting of 173,067 residents was chosen. Cancer incidence in this subcohort aged 30-84 y (N = 69,958) was analyzed. Cumulative radiation dose for each individual was estimated based on outdoor and indoor dosimetry of each household, taking into account sex- and age-specific house occupancy factors. Following 69,958 residents for 10.5 years on average, 736,586 person-years of observation were accumulated and 1,379 cancer cases including 30 cases of leukemia were identified by the end of 2005. Poisson regression analysis of cohort data, stratified by sex, attained age, follow-up interval, socio-demographic factors and bidi smoking, showed no excess cancer risk from exposure to terrestrial gamma radiation. The excess relative risk of cancer excluding leukemia was estimated to be -0.13 Gy-1 (95% CI: -0.58, 0.46). In site-specific analysis, no cancer site was significantly related to cumulative radiation dose. Leukemia was not significantly related to HBR, either. Although the statistical power of the study might not be adequate due to the low dose, our cancer incidence study, together with previously reported cancer mortality studies in the HBR area of Yangjiang, China, suggests it is unlikely that estimates of risk at low doses are substantially greater than currently believed.

Levels of cytochrome P450 (P450 or CYP) proteins immunoreactive to antibodies raised against human CYP1A2, 2A6, 2C9, 2E1, and 3A4, monkey CYP2B17, and rat CYP2D1 were determined in liver microsomes of rats, guinea pigs, dogs, monkeys, and humans. We also examined several drug oxidation activities catalyzed by liver microsomes of these animal species using eleven P450 substrates such as phenacetin, coumarin, pentoxyresorufin, phenytoin, S-mephenytoin, bufuralol, aniline, benzphetamine, ethylmorphine, erythromycin, and nifedipine; the activities were compared with the levels of individual P450 enzymes. Monkey liver P450 proteins were found to have relatively similar immunochemical properties by immunoblotting analysis to the human enzymes, which belong to the same P450 gene families. Mean catalytic activities (on basis of mg microsomal protein) of P450-dependent drug oxidations with eleven substrates were higher in liver microsomes of monkeys than of humans, except that humans showed much higher activities for aniline p-hydroxylation than those catalyzed by monkeys. However, when the catalytic activities of liver microsomes of monkeys and humans were compared on the basis of nmol of P450, both species gave relatively similar rates towards the oxidation of phenacetin, coumarin, pentoxyresorufin, phenytoin, mephenytoin, benzphetamine, ethylmorphine, erythromycin, and nifedipine, while the aniline p-hydroxylation was higher and bufuralol 1'-hydroxylation was lower in humans than monkeys. On the other hand, the immunochemical properties of P450 proteins and the activities of P450-dependent drug oxidation reactions in dogs, guinea pigs, and rats were somewhat different from those of monkeys and humans; the differences in these animal species varied with the P450 enzymes examined and the substrates used. The results presented in this study provide useful information towards species-related differences in susceptibilities of various animal species regarding actions and toxicities of drugs and xenobiotic chemicals.

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The characteristics and outcomes of PCP differ significantly depending on HIV status. The existence of underlying pulmonary diseases may be associated with the prognosis of HIV-negative patients with PCP.