Solution structure of RING finger-like domain of retinoblastoma-binding protein-6 (RBBP6) suggests it functions as a U-box

Retinoblastoma-binding protein-6 (RBBP6) plays a facilitating role, through its RING finger-like domain, in the ubiquitination of p53 by Hdm2 that is suggestive of E4-like activity. Although the presence of eight conserved cysteine residues makes it highly probable that the RING finger-like domain coordinates two zinc ions, analysis of the primary sequence suggests an alternative classification as a member of the U-box family, the members of which do not bind zinc ions. We show here that despite binding two zinc ions, the domain adopts a homodimeric structure highly similar to those of a number of U-boxes. Zinc ions could be replaced by cadmium ions without significantly disrupting the structure or the stability of the domain, although the rate of substitution was an order of magnitude slower than any previous measurement, suggesting that the structure is particularly stable, a conclusion supported by the high thermal stability of the domain. A hallmark of U-box-containing proteins is their association with chaperones, with which they cooperate in eliminating irretrievably unfolded proteins by tagging them for degradation by the proteasome. Using a yeast two-hybrid screen, we show that RBBP6 interacts with chaperones Hsp70 and Hsp40 through its N-terminal ubiquitin-like domain. Taken together with the structural similarities to U-box-containing proteins, our data suggest that RBBP6 plays a role in chaperone-mediated ubiquitination and possibly in protein quality control.     

The role of hospital-based cancer registries in low and middle income countries-The Nigerian Case Study

Background: The incidence of cancer continues to rise all over the world and current projections show that there will be 1.27 million new cases and almost 1 million deaths by 2030. In view of the rising incidence of cancer in sub-Saharan Africa, urgent steps are needed to guide appropriate policy, health sector investment and resource allocation. We posit that hospital based cancer registries (HBCR) are fundamental sources of information on the frequent cancer sites in limited resource regions where population level data is often unavailable. In regions where population based cancer registries are not in existence, HBCR are beneficial for policy and planning. Materials and methods: Nineteen of twenty-one cancer registries in Nigeria met the definition of HBCR, and from these registries, we requested data on cancer cases recorded from January 2009 to December 2010. 16 of the 19 registries (84%) responded. Data on year hospital was established; year cancer registry was established, no. of pathologists and types of oncology services available in each tertiary health facility were shown. Analysis of relative frequency of cancers in each HBCR, the basis of diagnosis recorded in the HBCR and the total number of cases recorded by gender was carried out. Results: The total number of cancers registered in these 11 hospital based cancer registries in 2009 and 2010 was 6484. The number of new cancer cases recorded annually in these hospital based cancer registries on average was 117 cases in males and I77 cases in females. Breast and cervical cancer were the most common cancers seen in women while prostate cancer was the commonest among men seen in these tertiary hospitals. Conclusion: Information provided by HBCR is beneficial and can be utilized for the improvement of cancer care delivery systems in low and middle income countries where there are no population based cancer registries.     

Peptidomimetics: A Synthetic Tool for Inhibiting Protein–Protein Interactions in Cancer

International Journal of Peptide Research and Therapeutics - Protein–protein interactions (PPI) are vital in modulating biochemical pathways in many biological processes. Inhibiting PPI is a...     

DNA Methylation Profiling across the Spectrum of HPV-Associated Anal Squamous Neoplasia

Background

Changes in host tumor genome DNA methylation patterns are among the molecular alterations associated with HPV-related carcinogenesis. However, there is little known about the epigenetic changes associated specifically with the development of anal squamous cell cancer (SCC). We sought to characterize broad methylation profiles across the spectrum of anal squamous neoplasia.

Methodology/Principal Findings

Twenty-nine formalin-fixed paraffin embedded samples from 24 patients were evaluated and included adjacent histologically normal anal mucosa (NM; n = 3), SCC-in situ (SCC-IS; n = 11) and invasive SCC (n = 15). Thirteen women and 11 men with a median age of 44 years (range 26–81) were included in the study. Using the SFP₁₀ LiPA HPV-typing system, HPV was detected in at least one tissue from all patients with 93% (27/29) being positive for high-risk HPV types and 14 (93%) of 15 invasive SCC tissues testing positive for HPV 16. Bisulfite-modified DNA was interrogated for methylation at 1,505 CpG loci representing 807 genes using the Illumina GoldenGate Methylation Array. When comparing the progression from normal anal mucosa and SCC-IS to invasive SCC, 22 CpG loci representing 20 genes demonstrated significant differential methylation (p<0.01). The majority of differentially methylated gene targets occurred at or close to specific chromosomal locations such as previously described HPV methylation “hotspots” and viral integration sites.

Conclusions

We have identified a panel of differentially methlylated CpG loci across the spectrum of HPV-associated squamous neoplasia of the anus. To our knowledge, this is the first reported application of large-scale high throughput methylation analysis for the study of anal neoplasia. Our findings support further investigations into the role of host-genome methylation in HPV-associated anal carcinogenesis with implications towards enhanced diagnosis and screening strategies.     

Enhanced production of succinic acid from methanol–organosolv pretreated Strophanthus preussii by recombinant Escherichia coli

Bioprocess and Biosystems Engineering - A biorefinery process for high yield production of succinic acid from biomass sugars was investigated using recombinant Escherichia coli. The major problem...     

Capacity to control oxidative stress-induced caspase-like activity determines the level of tolerance to salt stress in two contrasting maize genotypes

The response of two maize (Zea mays L.) genotypes, named GR (salt-tolerant) and SK (salt-sensitive), to salt stress (150 mM NaCl) was investigated under controlled environmental growth conditions. Genotype SK experienced more oxidative damage than the GR genotype when subjected to salt stress, which corresponded to higher O₂ ^? production rate and H₂O₂ content in the SK genotype than the GR genotype. Induction of caspase-like activity in response to salt stress was stronger in the SK genotype than in the GR genotype. On the other hand, induction of antioxidant enzyme activity to scavenge O₂ ^? and H₂O₂ in response to salt stress was weaker in the SK genotype than in the GR genotype. Consequently, the higher level of oxidative damage in the SK genotype in response to salt stress was manifested as more extensive cell death and biomass reduction in the SK genotype than it was in the GR genotype. Our results suggest that a direct relationship exists between salt stress-induced oxidative damage and cell death-inducing caspase-like activity, with tolerance to the salt stress being controlled by the efficiency of the plant antioxidant enzymes in limiting salt stress-induced oxidative damage and thus limiting cell death-inducing caspase-like activity.