Current Status of Human Papillomavirus-Related Head and Neck Cancer: From Viral Genome to Patient Care

Virologica Sinica - Human papillomavirus (HPV) infection identified as a definitive human carcinogen is increasingly being recognized for its role in carcinogenesis of human cancers. Up to...     

Parent Genotype and Environmental Factors Influence Introduction Success of the Critically Endangered Savannas Mint (Dicerandra immaculata var. savannarum)

Species previously unknown to science are continually discovered and some of these species already face extinction at the time of their discovery. Conserving new and rare species in these cases becomes a trial-and-error process and conservationists will attempt to manage them by using knowledge of closely related species, or those that fill the same ecological niche, and then adapting the management program as needed. Savannas Mint (Dicerandra immaculata Lakela var. savannarum Huck) is a perennial plant that was discovered in Florida scrub habitat at two locations in 1995, but is nearly extinct at these locations. We tested whether shade, leaf litter, propagation method, parent genotype, parent collection site, planting date, and absorbent granules influenced survival, reproduction, and recruitment of Savannas Mint in a population of 1,614 plants that we introduced between June 2006 and July 2009 into a state protected site. Survival and reproduction of introduced plants, and recruitment of new plants, was higher in microhabitats in full sun and no leaf litter and lower in partially shaded habitats. The two sites from which parent plants were collected differentially influenced survival and reproduction of introduced plants. These differences in survival and reproduction are likely due to underlying genetic differences. Differential survival of progeny from different parent genotypes further supports the idea that underlying genetics is an important consideration when restoring plant populations. The most successful progeny of parent genotypes had survival rates nearly 12 times higher than the least successful progeny. We speculate that many of these environmental and genetic factors are likely to influence allopatric congeners and other critically endangered gap specialists that grow in Florida scrub and our results can be used to guide their conservation.     

Bioengineering anabolic vitamin D-25-hydroxylase activity into the human vitamin D catabolic enzyme, cytochrome P450 CYP24A1, by a V391L mutation

CYP24A1 is a mitochondrial cytochrome P450 (CYP) that catabolizes 1α,25-dihydroxyvitamin D(3) (1α,25-(OH)(2)D(3)) to different products: calcitroic acid or 1α,25-(OH)(2)D(3)-26,23-lactone via multistep pathways commencing with C24 and C23 hydroxylation, respectively. Despite the ability of CYP24A1 to catabolize a wide range of 25-hydroxylated analogs including 25-hydroxyvitamin D(3), the enzyme is unable to metabolize the synthetic prodrug, 1α-hydroxyvitamin D(3) (1α-OH-D(3)), presumably because it lacks a C25-hydroxyl. In the current study we show that a single V391L amino acid substitution in the β3a-strand of human CYP24A1 converts this enzyme from a catabolic 1α,25-(OH)(2)D(3)-24-hydroxylase into an anabolic 1α-OH-D(3)-25-hydroxylase, thereby forming the hormone, 1α,25-(OH)(2)D(3). Furthermore, because the mutant enzyme retains its basal ability to catabolize 1α,25-(OH)(2)D(3) via C24 hydroxylation, it can also make calcitroic acid. Previous work has shown that an A326G mutation is responsible for the regioselectivity differences observed between human (primarily C24-hydroxylating) and opossum (C23-hydroxylating) CYP24A1. When the V391L and A326G mutations were combined (V391L/A326G), the mutant enzyme continued to form 1α,25-(OH)(2)D(3) from 1α-OH-D(3), but this initial product was diverted via the C23 hydroxylation pathway into the 26,23-lactone. The relative position of Val-391 in the β3a-strand of a homology model and the crystal structure of rat CYP24A1 is consistent with hydrophobic contact of Val-391 and the substrate side chain near C21. We interpret that the substrate specificity of V391L-modified human CYP24A1 toward 1α-OH-D(3) is enabled by an altered contact with the substrate side chain that optimally positions C25 of the 1α-OH-D(3) above the heme for hydroxylation.