Biology subjects

Levy, C. S.

Publications and source records attributed to Levy, C. S..

3 recordsLinked to original sources

bioRxiv2025

The constitutive oncogenic and signaling activities of phospha-tidylinositol 3-kinase (PI3K) isoforms p110β and p110δ

AbstractThe p110{beta} and p110{delta} isoforms of the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) show enhanced oncogenic and signaling activities as compared with the p110 protein. The adapter binding domains (ABDs) of p110{beta} and p110{delta} contain an isoform-specific PXXP mo- tif. Mutations of this PXXP to AXXA diminish the oncogenic and signaling activities. This loss of function can be compensated by placing a gain-of-function mutation in the helical domain of the P/A mutants. The P/A mutants still associate with the regulatory p85 subunit, but the affinity of this interaction is decreased. p110 with the ABD of either p110{beta} or p110{delta} shows an increase of oncogenic and signaling activities, whereas p110{beta} or p110{delta} with the ABD of p110 have greatly reduced oncogenic and signaling activities. Introducing the PXXP motif in the ABD of p110 re- sults in a significant gain of function. We conclude that the PXXP motif in the ABD of p110{beta} and p110{delta} is essential for the elevated oncogenic and signaling activities of these isoforms. We pro- pose that the PXXP motif in the ABD of p110{beta} and p110{delta} affects the interaction with the iSH2 domain of p85, shifting the regulatory SH2 domains into less effective inhibitory conformations.

cancer biology↗

bioRxiv2024

Perinatal liver inflammation is associated with persistent elevation of CXCL10 and its canonical receptor CXCR3 on common myeloid progenitors

Biliary atresia (BA) is a leading cause of liver failure in infants. Despite effective surgical drainage, patients with BA exhibit attenuated immune responses to childhood vaccines, suggesting there are long-lasting alterations to immune function. The perinatal liver is home to hematopoietic stem and progenitor cells (HSPCs) and serves as the epicenter for rapidly progressive and significantly morbid inflammatory diseases like BA. We have previously established the role of neonatal myeloid progenitors in the pathogenesis of perinatal liver inflammation (PLI) and hypothesize that PLI leads to long-term changes to HSPCs in mice that recovered from PLI. To test this hypothesis, we compared the changes that occur to HSPCs and mature myeloid populations in the bone marrow of adult mice during homeostasis and during PLI. Our results demonstrate that HSPCs from animals that recover from PLI ("PLI-recovered") undergo long-term expansion with a reduced proliferative capacity. Notably, PLI leads to persistent activation of common myeloid progenitors through the involvement of CXCL10 and its canonical receptor, CXCR3. Our data suggests that the CXCR3-CXCL10 axis may mediate the changes in HSPCs that lead to altered immune function observed in BA, providing support for a targetable pathway to mitigate the detrimental long-term immune effects observed in patients with BA.

immunology↗

bioRxiv2022

Neonatal hepatic myeloid progenitors expand and propagate liver inflammation in mice

Background and AimsBiliary atresia is a rapidly progressive pediatric inflammatory disease of the liver that leads to cirrhosis and necessitates liver transplantation. The rapid progression from liver injury to fulminant liver failure in children with biliary atresia suggests that factors specific to the perinatal hepatic environment are important for disease propagation. Hematopoietic stem and progenitor cells (HSPCs) serve as central hubs of inflammation and rely on inflammatory signals for their emigration from the liver to the bone marrow in neonatal mice. We hypothesized that HSPCs are critical for the propagation of perinatal liver inflammation (PLI). MethodsNewborn BALB/c mice were injected intraperitoneally with 1.5x106 focus forming units of Rhesus Rotavirus (RRV) to induce PLI or with PBS as control. Livers from RRV- and PBS-injected mice were compared using histology and flow cytometry. To determine the effects of HSPCs on perinatal inflammation, RRV-infected neonatal mice were injected with anti-CD47 and anti-CD117 to deplete HSPCs. ResultsRRV-induced PLI led to a significant increase in the number of common myeloid progenitors (Flt3+ CMPs: PBS=4426{+/-}247.2 vs RRV=9856{+/-}2009, p=0.0316; Flt3- CMPs: PBS=3063{+/-}254.9 vs RRV=9743{+/-}1539, p=0.0012). We corroborated these findings by observing a significant increase in CD34+ hematopoietic progenitors/cm2 in histological sections of RRV-infected livers (PBS=4.977{+/-}2.573 vs RRV=27.09{+/-}12.49, p=0.0075). Elimination of progenitors through antibody-mediated myeloablation rescued animals from PLI and significantly increased survival (RRV+isotype control 55.56% vs RRV+myeloablation 94.12%, Chi-test=0.01). ConclusionsThese data demonstrate that RRV causes expansion of HSPCs and propagates PLI. Targeting of HSPCs may be useful in preventing and treating neonatal inflammatory diseases of the liver like biliary atresia. SYNOPSISHematopoietic progenitors reside in juvenile mouse livers even after the main site of hematopoiesis has shifted to the bone marrow. These progenitors are critical for the pathogenesis of perinatal liver inflammation as myeloablation rescues animals from disease.

immunology↗