Biology subjects

Russo, L. C.

Publications and source records attributed to Russo, L. C..

3 recordsLinked to original sources

bioRxiv2024

Dual Specificity Phosphatase 3 knockdown drives myeloid leukemia cells to differentiate into macrophages and polarize

The dual-specificity phosphatase 3 (DUSP3) has been implicated in the maintenance of genomic stability, cell cycle, proliferation, and differentiation. Recently we reported an important role of the interaction between DUSP3 and nucleophosmin (NPM) proteins on the regulation of the p53 actions to maintain genomic stability. Since both p53 and NPM often have mutations related to a diverse set of leukemia, this work aimed to evaluate the roles of DUSP3 in the differentiation of two acute myeloid leukemia cell lines not expressing the p53 protein, and the potential correlations with NPM expression. The results demonstrated higher levels of DUSP3 in THP-1 cells compared to HL-60 cells under basal conditions. After PMA-induced differentiation into macrophages, only HL-60 cells presented a dramatic decrease in DUSP3 and NPM proteins expression. The permanent DUSP3 knockdown in THP-1 and HL-60 cells contributed to their differentiation and non-classical polarization after PMA exposure, since the CD14, MHCII, and CD163 markers were decreased whereas the CD11b and CD206 markers were increased. Bioinformatics analyses identified that the negative regulation of the npm1 and dusp3 genes correlates with the reduced survival of patients with acute myeloid leukemia (AML) and the strong positive correlation existing between the expression of these two genes is progressively lost according to the degree of maturation of the myeloid cells. These results suggest DUSP3 plays regulatory roles of differentiation and polarization of myeloid cells, and its association with NPM expression levels may allow a better understanding of mechanisms involved in leukemia and treatment resistance. HIGHLIGHTSDUSP3 knockdown drives myeloid leukemia cells to differentiation DUSP3 silencing drives myeloid leukemia cells to macrophage polarization DUSP3 and NPM association are potential targets for leukemia treatment and resistance

immunology↗

bioRxiv2024

Temporal Analysis of Pituitary Transcriptional Dynamics in Mice Models of Hypopituitarism During Postnatal Development

Congenital hypopituitarism is characterized by deficient pituitary hormone production, affecting growth and development. The molecular mechanisms underlying pituitary development and dysfunction in hypopituitarism remain incompletely understood. We investigated the expression of key pituitary development markers in three mouse models of congenital hypopituitarism, with molecular alterations in the Prop1, Pou1f1, and GSU genes across critical postnatal developmental stages: neonatal (P0), early postnatal (P7), pubertal (4 weeks), and adult (8 weeks). We assessed mRNA and protein levels of the pituitary stem cell markers (SOX2), proliferation marker (Ki67) and pituitary hormones, correlating these with pituitary function and disease. Prop1 deficiency led to significant upregulation of Sox2 and Hesx1 during early postnatal development and in adulthood, diverging from the relatively stable expression patterns observed in Pou1f1 and GSU mutants. Despite some variations, overall Sox2 and Ki67 expression profiles were similar between Prop1 and Pou1f1 mutants. Prop1 mutants exhibited altered pituitary morphology, with increased SOX2-positive cells suggesting disrupted stem cell migration. During the pubertal period, a subset of hormone-producing cells in Prop1 mutants co-expressed SOX2, indicating differentiation without restoring normal pituitary function. Hormone analysis revealed transient gonadotropin production and secretion during sexual maturation in Prop1 mutants, without recovery of the hypogonadal phenotype. Our study elucidates the complex transcriptional dynamics of pituitary development markers in mouse models of congenital hypopituitarism, highlighting the pivotal role of Prop1 in regulating stem cell marker expression. The distinct transcriptional responses in Prop1 mutants during key developmental windows shed light on the mechanisms of pituitary dysgenesis and the persistent inability to fully recover pituitary function, despite transient hormonal changes during puberty. These insights contribute to a better understanding of pituitary development and dysfunction in congenital hypopituitarism.

developmental biology↗

bioRxiv2021

The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signalling

SARS-CoV-2 non-structural protein 3 (Nsp3) contains a macrodomain that is essential for virus replication and is thus an attractive target for drug development. This macrodomain is thought to counteract the host interferon (IFN) response, an important antiviral signalling cascade, via the removal of ADP-ribose modifications catalysed by host poly(ADP-ribose) polymerases (PARPs). Here, we show that activation of the IFN response induces ADP-ribosylation of host proteins and that ectopic expression of the SARS-CoV-2 Nsp3 macrodomain reverses this modification in human cells. We further demonstrate that this can be used to screen for cell-active macrodomain inhibitors without the requirement for BSL-3 facilities. This IFN-induced ADP-ribosylation is dependent on the PARP9/DTX3L heterodimer, but surprisingly the expression of Nsp3 macrodomain or PARP9/DTX3L deletion do not impair STAT1 phosphorylation or the induction of IFN-responsive genes. Our results suggest that PARP9/DTX3L-dependent ADP-ribosylation is a downstream effector of the host IFN response and that the cellular function of the SARS-CoV-2 Nsp3 macrodomain is to hydrolyse this end product of IFN signalling, and not to suppress the IFN response itself.

molecular biology↗