Biology subjects

Karnan, S.

Publications and source records attributed to Karnan, S..

4 recordsLinked to original sources

bioRxiv2024

Targeting fatty acid synthase suppresses tumor development in NF2/CDKN2A-deficient malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an uncommon yet deadly cancer linked to asbestos exposure. The lack of effective early diagnosis and treatment leads to reduced life expectancy among patients with MPM. This study is aimed to identify a novel molecular target inhibitor to develop more effective therapeutics for MPM. Our drug screening assay showed that the fatty acid synthase (FASN) inhibitor cerulenin demonstrates strong and selective anti-proliferative properties against NF2/CDKN2A(p16)-deficient MPM cells, surpassing the effects of cisplatin or pemetrexed. FASN protein is frequently detected in NF2/p16-deficient MPM tumor-derived tissues (15/15, 100%), but rarely in NF2/p16-intact MPM tumors (8/25, 32%). Notably, cerulenin administration successfully reduced the growth of NF2/p16-deficient MPM tumors in xenografted mice. Cerulenin inhibits mitochondrial fission by targeting dynamin-related protein 1 (DRP1) in NF2/p16-deficient cells. Moreover, the disruption of the FASN gene leads to increased ubiquitination of DRP1. These findings suggest that FASN might play a role in the tumorigenesis of MPM cells through the regulation of mitochondrial dynamics. This research offers a novel perspective on the potential development of precision medicine for MPM.

cancer biology↗

bioRxiv2022

A mouse model of insomnia with sleep apnea

Obstructive sleep apnea (OSA) patients are exposed to nighttime hypoxia during sleep by intermittent airway closure and feel daytime strong sleepiness. Strangely, insomnia co-occur in some OSA patients, which is called co-morbid insomnia and sleep apnea (COMISA). Here, we show activity responses to daytime hypoxia (DHx) in nocturnal mice were comparable to daytime sleepiness and co-occurring nighttime insomnia in COMISA. DHx reduced activity in active phase (AP) and increased following activity in activity ending phase (AEP). This down-and-up activity response (DUR) by DHx was also observed in molecular clock deficient Cry1 and Cry2 double knockout mice (CryDKO) expressing nighttime activity rise under light-dark cycle (LD) and not observed in arrhythmic CryDKO under constant darkness (DD). When daytime timing hypoxia was exposed at transition from LD to DD, about every 6 h down and up and down wavelike activity responses appeared in arrhythmic CryDKO. Results indicate this wavelike response and AP activity overlap and cause DUR in rhythmic mice. DHx increased plasma corticosterone and this increase antagonized AP activity reduction by DHx. DHx reduced forebrain adenosine and morning adenosine inhibition by caffeine induced DUR. Adenosine inhibition by caffeine or istradefylline at transition from LD to DD induced wavelike response in CryDKO. It is possible that wavelike response is damped oscillation because, interestingly, chronic caffeine treatment induced circasemidian and/or circadian activity rhythms in arrhythmic CryDKO. Evening caffeine attenuated DUR by DHx, which suggested adenosine inhibition chronotherapy may improve OSA/COMISA symptoms. Our animal model will be useful to understand COMISA. SignificanceObstructive sleep apnea patients (OSA) are exposed to nighttime hypoxia during sleep. OSA feels daytime strong sleepiness and increases risk of many diseases. Insomnia occurs in not a few OSA, which is called comorbid insomnia and sleep apnea (COMISA). We show here a mouse model of COMISA. In mice, daytime hypoxia exposure induced following down and up activity response (DUR), activity reduction in active phase and increase in activity ending phase, which corresponded to sleepiness and insomnia in COMISA. We found DUR was clock gene independent and might be driven by circasemidian system. Glucocorticoid and forebrain adenosine response were involved in DUR. Caffeine chronotherapy was effective in DUR. Our model may be useful to understand COMISA.

physiology↗

bioRxiv2022

LUZP1 regulates the constriction velocity of the contractile ring during cytokinesis

There has been a great deal of research on cell division and its mechanisms; however, its processes have not yet been entirely elucidated. To find novel proteins that regulate cell division, we performed the screening using siRNAs and/or the expression plasmid of the target genes and identified leucine zipper protein 1 (LUZP1). Recent studies have shown that LUZP1 interacts with various proteins and stabilizes the actin cytoskeleton; however, the function of LUZP1 in mitosis is not known. In this study, we found that LUZP1 colocalized with the chromosomal passenger complex (CPC) at the centromere in metaphase and at the central spindle in anaphase and that these LUZP1 localizations were regulated by CPC activity and kinesin family member 20A (KIF20A). Mass spectrometry analysis identified that LUZP1 interacted with death-associated protein kinase 3 (DAPK3), one regulator of the cleavage furrow ingression in cytokinesis. In addition, we found that LUZP1 also interacted with myosin light chain 9 (MYL9), a substrate of DAPK3, and comprehensively inhibited MYL9 phosphorylation by DAPK3. In line with a known role for MYL9 in the actin-myosin contraction, LUZP1 suppression accelerated the constriction velocity at the division plane in our timelapse analysis. Our study indicates that LUZP1 is a novel regulator for cytokinesis that regulates the constriction velocity of the contractile ring.

cell biology↗

bioRxiv2019

Tandem paired nicking promotes precise genome editing with scarce interference by p53

Targeted knock-in mediated by double-stranded DNA cleavage is accompanied by unwanted insertions and deletions (indels) at on-target and off-target sites. A nick-mediated approach scarcely generates indels but exhibits reduced efficiency of targeted knock-in. Here, we demonstrate that tandem paired nicking, a method for targeted knock-in involving two Cas9 nickases that create nicks at the homologous regions of the donor DNA and the genome in the same strand, scarcely creates indels at the edited genomic loci, while permitting the efficiency of targeted knock-in largely equivalent to that of the Cas9 nuclease-based approach. Tandem paired nicking seems to accomplish targeted knock-in via DNA recombination analogous to Hollidays model, and creates intended genetic changes in the genome without introducing additional nucleotide changes such as silent mutations. Targeted knock-in through tandem paired nicking neither triggers significant p53 activation nor occurs preferentially in p53-suppressed cells. These properties of tandem paired nicking demonstrate its utility in precision genome engineering.

molecular biology↗