St. Jude Children's Research Hospital

About: St. Jude Children's Research Hospital is a healthcare organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Virus. The organization has 9344 authors who have published 19233 publications receiving 1233399 citations. The organization is also known as: St. Jude Children's Hospital & St. Jude Hospital.

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease.

Abstract: Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer’s disease (AD) has facilitated advancement of the amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc box-dependent-interacting protein 1, clusterin, and presenilin-1. U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein. Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.

Childhood acute lymphoblastic leukaemia – current status and future perspectives

Abstract: The current cure rate of 80% in childhood acute lymphoblastic leukaemia attests to the effectiveness of risk-directed therapy developed through well-designed clinical trials. In the past decade there have been remarkable advances in the definition of the molecular abnormalities involved in leukaemogenesis and drug resistance. These advances have led to the development of promising new therapeutic strategies, including agents targeted to the molecular lesions that cause leukaemia. The importance of host pharmacogenetics has also been recognised. Thus, genetic polymorphisms of certain enzymes have been linked with host susceptibility to the development of de novo leukaemia or therapy-related second cancers. Furthermore, recognition of inherited differences in the metabolism of antileukaemic agents has provided rational selection criteria for optimal drug dosages and scheduling. Treatment response assessed by measurements of submicroscopic leukaemia (minimal residual disease) has emerged as a powerful and independent prognostic indicator for gauging the intensity of therapy. Ultimately, treatment based on biological features of leukaemic cells, host genetics, and the amount of residual disease should improve cure rates further.

Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression

Abstract: Alterations in normal protein biogenesis and the resulting accumulation of improperly folded proteins in the endoplasmic reticulum (ER) trigger a stress response that up-regulates the expression of ER chaperones, while coordinately repressing overall protein synthesis and causing cell-cycle arrest Activation of this unfolded protein response (UPR) in mouse NIH 3T3 fibroblasts with the glycosylation inhibitor tunicamycin led to a decline in cyclin D- and E-dependent kinase activities and to G1 phase arrest Cyclin D1 protein synthesis was rapidly inhibited by tunicamycin treatment However, the drug did not significantly affect the mitogen-dependent activities of the extracellular signal-activated protein kinases ERK1 and ERK2 or the level of cyclin D1 mRNA until much later in the response Therefore, the UPR triggers a signaling pathway that blocks cyclin D1 translation despite continuous mitogenic stimulation Enforced overexpression of cyclin D1 in tunicamycin-treated cells maintained cyclin D- and E-dependent kinase activities and kept cells in cycle in the face of a fully activated UPR Translational regulation of cyclin D1 in response to ER stress is a mechanism for checkpoint control that prevents cell-cycle progression until homeostasis is restored