Biology subjects

Rattani, A.

Publications and source records attributed to Rattani, A..

3 recordsLinked to original sources

bioRxiv2025

The Wnt/APC destruction complex targets SREBP2 in a β-catenin-independent pathway to control cholesterol metabolism

APC, the core scaffold of the Wnt destruction complex, targets the transcriptional co-activator {beta}-catenin for proteolysis. There is no convincing evidence that APC directs degradation of other substrates. Using a reconstituted cytosolic extract-based system and complementary in vivo and cellular assays, we show that SREBP2, the master regulator of cholesterol biosynthesis, is a direct APC-AXIN1 substrate. APC-dependent SREBP2 degradation is conserved in Xenopus embryos, mouse colon, and human colorectal cancer cells and restricts SREBP2 target-gene expression, cholesterol synthesis, and tissue cholesterol levels. Mechanistically, APC and AXIN1 promote SREBP2 degradation via a conserved phosphodegron, which marks SREBP2 for ubiquitination by the E3 enzyme, FBXW7. Like {beta}-catenin, SREBP2 is stabilized by extracellular Wnt ligands; unlike {beta}-catenin, its regulation is independent of GSK3{beta} and CK1 and requires the entire APC mutational cluster region (MCR), whereas {beta}-catenin turnover can operate with only a partial MCR. These findings define a {beta}-catenin-independent branch of Wnt signaling that couples APC to sterol metabolism, providing a mechanistic rationale to target the mevalonate/SREBP2 axis in APC-mutant colorectal cancer.

biochemistry↗

bioRxiv2020

Loss of Sister Kinetochore Co-orientation and Peri-centromeric Cohesin Protection after Meiosis I Depends on Cleavage of Centromeric REC8

Protection of peri-centromeric REC8 cohesin from separase and sister kinetochore attachment to microtubules emanating from the same spindle pole (co-orientation) ensure that sister chromatids remain associated after meiosis I. Both features are lost during meiosis II, when sister kinetochores bi-orient and lose peri-centromeric REC8 protection, resulting in sister chromatid disjunction and the production of haploid gametes. By transferring spindle-chromosome complexes (SCCs) between meiosis I and II cells, we have discovered that both sister kinetochore co-orientation and peri-centromeric cohesin protection depend on the SCC and not the cytoplasm. Moreover, the catalytic activity of separase at meiosis I is necessary not only for converting kinetochores from a co-to a bi-oriented state but also for deprotection of peri-centromeric cohesin and that cleavage of REC8 may be the key event. Crucially, we show that selective cleavage of REC8 in the vicinity of kinetochores is sufficient to destroy co-orientation in univalent chromosomes, albeit not in bivalents where resolution of chiasmata through cleavage of Rec8 along chromosome arms may also be required.

cell biology↗

bioRxiv2019

Association and impact of hypertension defined using the 2017 AHA/ACC guidelines on the risk of atrial fibrillation in the Atherosclerosis Risk in Communities Study

Hypertension is an established risk factor for the development of atrial fibrillation (AF). We evaluated the association and population impact of hypertension, defined using the new 2017 guidelines, on risk of AF. In this analysis, we included 9,207 participants in the Atherosclerosis Risk in Communities study without history of cardiovascular disease or diabetes. Participants underwent blood pressure measurements at baseline and their antihypertensive medication use was assessed. AF was ascertained from study electrocardiograms, hospital records and death certificates. Cox proportional models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of AF among individuals with hypertension based on the JNC7 and 2017 ACC/AHA guidelines. Poisson models were used to obtain risk ratios and calculate population-attributable fractions (PAFs). We identified 1,573 cases of incident AF during 22.1 years of mean follow-up. Prevalence of hypertension was 29% and 43% under the JNC7 and 2017 ACC/AHA definitions, respectively. HRs (95%CI) of AF in hypertensives versus non-hypertensives were 1.54 (1.39, 1.72) and 1.45 (1.31, 1.61) after multivariable adjustment under the old and new guidelines, respectively. The corresponding PAF (95%CI) using the old and new guidelines were 12% (9%, 14%) and 14% (10%, 18%), respectively. Overall, our analysis shows that even though the prevalence of hypertension using the new criteria is 50% higher than with the old criteria, this does not translate into meaningful increases in AF attributable to hypertension. These results suggest that prevention or treatment of hypertension based on the new (versus old) guidelines may have limited impact on AF incidence.

epidemiology↗