Metabolic control of G1–S transition: cyclin E degradation by p53-induced activation of the ubiquitin–proteasome system

When mitochondrial function fails, p53 is recruited to get rid of cyclin E, bringing mitotic progression to a halt

Metabolic control of G1-S transition: cyclin E degradation by p53-induced activation of the ubiquitin-proteasome system.

Cell cycle progression is precisely regulated by diverse extrinsic and intrinsic cellular factors. Previous genetic analysis in Drosophila melanogaster has shown that disruption of the mitochondrial electron transport chain activates a G1-S checkpoint as a result of a control of cyclin E by p53. This regulation does not involve activation of the p27 homologue dacapo in flies. We demonstrate that regulation of cyclin E is not at the level of transcription or translation. Rather, attenuated mitochondrial activity leads to transcriptional upregulation of the F-box protein archipelago, the Fbxw7 homologue in flies. We establish that archipelago and the proteasomal machinery contribute to degradation of cyclin E in response to mitochondrial dysfunction. Our work provides in vivo genetic evidence for p53-mediated integration of metabolic stress signals, which modulate the activity of the ubiquitin-proteasome system to degrade cyclin E protein and thereby impose cell cycle arrest

Absence of hemochromatosis associated Cys282Tyr HFE gene mutation and low frequency of hemochromatosis phenotype in nonalcoholic chronic liver disease patients in India

Background and Aim: Hereditary hemochromatosis (HHC) is an autosomal recessive disorder causing primary iron overload syndrome and chronic liver disease (CLD). This genetic disease is commonly associated with C282Y mutation of the HFE gene, commonly seen in the Northern European population. Minor reports on HHC are available from Asia, however, so far no genetic study is available from India. We prospectively studied the prevalence of C282Y mutation in CLD patients and healthy subjects in a tertiary care referral center in India. Methods: A total of 249 consecutive biopsy proven CLD (HBV = 112, HCV = 72, cryptogenic = 65) patients and 134 age matched healthy controls were included. Cases of secondary iron overload, pregnancy, chronic alcoholism, age < 30 years and hepatocellular carcinoma (HCC) were excluded. A transferrin saturation index (TSI) of >60% was suggestive of a phenotypic presentation of HHC. C282Y mutation was studied by restriction fragment length polymorphism (RFLP) using genomic DNA. The 387 bp fragment obtained after polymerase chain reaction was digested with 10 units of endonuclease Rsa1. The mutation was detected by creation of an additional restriction site, giving rise to fragments of 247 111 and 29 bp. Results: While the mean TSI was comparable, serum ferritin was significantly higher in CLD patients compared to controls (38 ± 16%vs 28 ± 13%; p = not significant (NS), and 125 ± 18 vs 42 ± 25 ng/mL; p < 0.001). A TSI of >60% was detected in 24 (9.64%) patients. Only one restriction site was found for endonuclease Rsa1, giving rise to two fragments of 247 and 140 bp, suggesting absence of C282Y mutation in the HFE gene in all patients. Conclusions: Almost 10% of nonalcoholic CLD patients in India have iron overload, but this is independent of C282Y mutation of the HFE gene. Large population based studies are recommended to investigate the prevalence of this rare disorder in India

Prevalence and profile of mutations associated with lamivudine therapy in Indian patients with chronic hepatitis B in the surface and polymerase genes of hepatitis B virus

Lamivudine results in the selection of resistant hepatitis B virus (HBV) variants. Because the surface gene of HBV overlaps completely the polymerase gene, the incidence and profile of surface and polymerase gene mutations were investigated prospectively in chronic HBV patients who were on lamivudine therapy. Twenty-six patients with chronic liver disease confirmed histologically were included in this study. Extracted HBV DNA from sera samples were subjected to PCR amplification for the mutation prone regions of the surface and polymerase genes of the HBV genome. The emergence of mutant forms and biochemical derangements were studied carefully during the course of the therapy. In six of 26 (23%) patients, mutations emerged on lamivudine therapy. YM552I/VDD resistant mutants were observed in one (6%) and five (29%) patients at Month 12 and 18, respectively, out of 17 patients, who had completed more than 9 months of therapy. The mean time of emergence of resistance was 16.4±6.8 months. In three of the five patients, emergence of YM552I/VDD mutation was accompanied with a rise in HBV DNA levels. In two patients, mutations were noticed at the end of the viral breakthrough; when the DNA level went down to undetectable levels (<0.5 pg/mL). In two patients, normal ALT levels were found at the time of emergence of the YMDD mutation. YM552I/VDD mutations were observed in 43% of HBeAg positive and 20% of anti-HBe positive patients (P=ns). Although the 'a'-determinant region was found to be unaffected; in one patient, a novel pattern due to emergence of YIDD mutant was observed; the corresponding aa in the S-ORF turned to a stop codon. In summary, the frequency of emergence of YM552I/VDD mutations was 29% at Month 18 in the Indian patients. The presence of normal ALT and low levels of HBV DNA do not exclude the existence of resistant mutants. Novel mutations in the S-ORF, which lead to premature surface gene termination might affect the production of HBsAg and need further study

Diabetes and tuberculosis: a review of the role of optimal glycemic control

<p>Abstract</p> <p>Developing countries shoulder most of the burden of diabetes and tuberculosis. These diseases often coexist. Suboptimal control of diabetes predisposes the patient to tuberculosis, and is one of the common causes of poor response to anti-tubercular treatment. Tuberculosis also affects diabetes by causing hyperglycemia and causing impaired glucose tolerance. Impaired glucose tolerance is one of the major risk factors for developing diabetes. The drugs used to treat tuberculosis (especially rifampicin and isoniazid) interact with oral anti-diabetic drugs and may lead to suboptimal glycemic control. Similarly some of the newer oral anti-diabetic drugs may interact with anti-tuberculosis drugs and lower their efficacy. Therefore diabetes and tuberculosis interact with each other at multiple levels – each exacerbating the other. Management of patients with concomitant tuberculosis and diabetes differs from that of either disease alone. This article reviews the association between diabetes and tuberculosis and suggests appropriate management for these conditions.</p