Biomedical subjects

Julie Lessard

Publications and source records attributed to Julie Lessard.

7 recordsLinked to original sources

PubMed2006

E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells.

The Polycomb group gene Bmi1 is essential for the proliferation of neural and hematopoietic stem cells. Much remains to be learned about the pathways involved in the severe hematopoietic phenotype observed in Bmi1 homozygous mutant mice except for the fact that loss of p53 or concomitant loss of p16(Ink4a) and p19(Arf) functions achieves only a partial rescue. Here we report the identification of E4F1, an inhibitor of cellular proliferation, as a novel BMI1-interacting partner in hematopoietic cells. We provide evidence that Bmi1 and E4f1 genetically interact in the hematopoietic compartment to regulate cellular proliferation. Most importantly, we demonstrate that reduction of E4f1 levels through RNA interference mediated knockdown is sufficient to rescue the clonogenic and repopulating ability of Bmi1(-/-) hematopoietic cells up to 3 mo post-transplantation. Using cell lines and MEF, we also demonstrate that INK4A/ARF and p53 are not essential for functional interaction between Bmi1 and E4f1. Together, these findings identify E4F1 as a key modulator of BMI1 activity in primitive hematopoietic cells.

Animals↗

PubMed2006

Stage-specific expression of the Atce1/Tisp40alpha isoform of CREB3L4 in mouse spermatids.

The maturation of haploid spermatids into spermatozoa relies on the timely production of proteins required for spermatid differentiation. The mammalian CREB3L4 (cAMP responsive element binding protein 3-like 4) gene encodes a bZIP transcription factor that associates with the membrane of the endoplasmic reticulum. CREB3L4 is presumed to play an important role in protein maturation via its involvement in the cellular response to endoplasmic reticulum stress. In mice, the Creb3l4 gene gives rise to 2 distinct classes of mRNAs through the use of alternate promoters. Transcripts that initiate upstream of the first coding exon encode a 370-amino acid (aa) protein designated Tisp40beta, whereas transcripts that initiate downstream of the first coding exon encode Atce1/Tisp40alpha, a truncated (315-aa) form of Tisp40beta. In the mouse testis, Creb3l4 transcripts are known to be expressed exclusively in postmeiotic spermatids but the presence of CREB3L4 protein in spermatids has not been formally demonstrated. We produced an antibody directed against the carboxy terminus of mouse CREB3L4 and used it in immunostaining experiments to document that CREB3L4 protein accumulates in post-meiotic spermatids in a stage-specific manner. Moreover, we show that Atce1/Tisp40alpha is the major form of CREB3L4 in mouse testis. These findings suggest that testis-specific isoforms of Creb3l4 could play an important role in spermatid differentiation.

Animals↗

PubMed2005

Penetrating thoracoabdominal injuries in Quebec: implications for surgical training and maintenance of competence.

BACKGROUND: The frequency of penetrating trauma is low in Canada. Current recommendations for the care of patients with penetrating injuries originate from inner city trauma centres with a high volume of such injuries and may not apply to Canada. The purpose of this study was to review the incidence and treatment of penetrating thoracoabdominal injuries in the 4 tertiary trauma centres in Quebec. METHODS: We identified all patients with penetrating thoracic or abdominal injuries who were taken to any of the 4 tertiary trauma centres in the province of Quebec between Apr. 1, 1998, and Mar. 31, 2001. Patients who were dead on arrival were excluded. Only patients with an Abbreviated Injury Scale of 2 or greater for the thoracic or abdominal regions were included. RESULTS: In total, 245 patients meeting our inclusion criteria were identified. Of these 223 (91%) were male. The mean (and standard deviation) age was 33.8 (13.2) years; range 15-90 years. The median Injury Severity Score was 10 (range 4-75). Overall in-hospital mortality was 6.9%. There were 203 patients (82.8%) with thoracic injuries and 192 patients (78.4%) with abdominal injuries. Fifty (20.4%) of these patients had injuries to both regions. A thoracotomy was carried out in 48 (31.4%) of 153 patients who had injuries to the thorax, and the abdomen was explored in 133 (93.7%) of the 142 patients with abdominal injuries. The incidence of these injuries in the study period varied from 3 to 49 cases per centre. CONCLUSIONS: The annual incidence of penetrating thoracoabdominal injuries is extremely low in all 4 of Quebec's tertiary trauma centres, and the number of thoracoabdominal procedures is even lower. Such a low exposure may jeopardize education and clinical competence. We need to rethink our educational strategies both for residents and for continuing medical education. New approaches to training and maintenance of competence must be developed.

Abdominal Injuries↗

PubMed2004

Genetic programs regulating HSC specification, maintenance and expansion.

All mature blood cells originate from a small population of self-renewing pluripotent hematopoietic stem cells (HSCs). The capacity to self-renew characterizes all stem cells, whether normal or neoplastic. Interestingly, recent studies suggest that self-renewal is essential for tumor cell maintenance, implicating that this process has therapeutic relevance. Unfortunately, the molecular bases for self-renewal of vertebrate cells remain poorly defined. This article will focus on the developmental mechanisms underlying fetal and adult HSC homeostasis. Specifically, distinctions between genetic programs regulating HSC specification (identity), self-renewal (in both fetal and adult) and differentiation/commitment will be discussed with a special emphasis on transcriptional and chromatin regulators.

Acute Disease↗

PubMed2004

Are genetic determinants of asymmetric stem cell division active in hematopoietic stem cells?

Stem cells have acquired a golden glow in the past few years as they represent possible tools for reversing the damage wreak on organs. These cells are found not only in major regenerative tissues, such as the epithelia, blood and testes, but also in 'static tissues', such as the nervous system and liver, where they play a central role in tissue growth and maintenance. The mechanism by which stem cells maintain populations of highly differentiated, short-lived cells seems to involve a critical balance between alternate fates: daughter cells either maintain stem cell identity or initiate differentiation. Recent studies in lower organisms have unveiled the regulatory mechanisms of asymmetric stem cell divisions. In these models, the surrounding environment likely provides key instructive signals for the cells to choose one fate over another. Our understanding now extends to the intrinsic mechanisms of cell polarity that influence asymmetrical stem cell divisions. This article focuses on the genetic determinants of asymmetric stem cell divisions in lower organisms as a model for studying the process of self-renewal of mammalian hematopoietic stem cells.

Animals↗

PubMed2003

Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells.

An emerging concept in the field of cancer biology is that a rare population of 'tumour stem cells' exists among the heterogeneous group of cells that constitute a tumour. This concept, best described with human leukaemia, indicates that stem cell function (whether normal or neoplastic) might be defined by a common set of critical genes. Here we show that the Polycomb group gene Bmi-1 has a key role in regulating the proliferative activity of normal stem and progenitor cells. Most importantly, we provide evidence that the proliferative potential of leukaemic stem and progenitor cells lacking Bmi-1 is compromised because they eventually undergo proliferation arrest and show signs of differentiation and apoptosis, leading to transplant failure of the leukaemia. Complementation studies showed that Bmi-1 completely rescues these proliferative defects. These studies therefore indicate that Bmi-1 has an essential role in regulating the proliferative activity of both normal and leukaemic stem cells.

Animals↗

PubMed2003

Polycomb group genes as epigenetic regulators of normal and leukemic hemopoiesis.

Epigenetic modification of chromatin structure underlies the differentiation of pluripotent hemopoietic stem cells (HSCs) into their committed/differentiated progeny. Compelling evidence indicates that Polycomb group (PcG) genes play a key role in normal and leukemic hemopoiesis through epigenetic regulation of HSC self-renewal/proliferation and commitment. The PcG proteins are constituents of evolutionary highly conserved molecular pathways regulating cell fate in several other tissues through diverse mechanisms, including 1) regulation of self-renewal/proliferation, 2) regulation of senescence/immortalization, 3) interaction with the initiation transcription machinery, 4) interaction with chromatin-condensation proteins, 5) modification of histones, 6) inactivation of paternal X chromosome, and 7) regulation of cell death. It is therefore not surprising that PcG genes lead to pleiotropic phenotypes when mutated and have been associated with malignancies in several systems in both mice and humans. Although much remains to be learned regarding the PcG mechanism(s) of action, advances in identifying the functional domains and enzymatic activities of these multimeric protein complexes have provided insights into how PcG proteins accomplish such processes. Some of the new insights into a role for the PcG cellular memory system in regulating normal and leukemic hemopoiesis are reviewed here, with special emphasis on their potential involvement in epigenetic regulation of gene expression through modification of chromatin structure.

Animals↗