Apoptosis is a physiological cell suicide program that is critical for the development and maintenance of healthy tissues. Dysregulation of cell death pathways occur in cancer, autoimmune and immunodeficiency diseases, reperfusion injury after ischemic episodes, and in neurodegenerative disorders. Thus, proteins involved in apoptosis regulation are of intense biological interest and many are attractive therapeutic targets. This review discusses the Inhibitor of Apoptosis (IAP) family of proteins. First discovered in baculoviruses, IAPs were shown to be involved in suppressing the host cell death response to viral infection. Interestingly, ectopic expression of some baculoviral IAPs blocks apoptosis in mammalian cells, suggesting conservation of the cell death program among diverse species and commonalities in the mechanism used by the IAPs to inhibit apoptosis. Although the mechanism used by the IAPs to suppress cell death remains debated, several studies have provided insights into the biochemical functions of these intriguing proteins. Moreover, a variety of reports have suggested an important role for the IAPs in some human diseases.

/pdf/iap-family-proteins-suppressors-of-apoptosis-49tztuyxcj.pdf

IAP family proteins—suppressors of apoptosis

https://www.cell.com/cell/pdf/S0092-8674(00)80371-2.pdf

CRM1 Is an Export Receptor for Leucine-Rich Nuclear Export Signals

▪ Abstract The compartmentation of eukaryotic cells requires all nuclear proteins to be imported from the cytoplasm, whereas, for example, transfer RNAs, messenger RNAs, and ribosomes are made in the nucleus and need to be exported to the cytoplasm. Nuclear import and export proceed through nuclear pore complexes and can occur along a great number of distinct pathways, many of which are mediated by importin β-related nuclear transport receptors. These receptors shuttle between nucleus and cytoplasm, and they bind transport substrates either directly or via adapter molecules. They all cooperate with the RanGTPase system to regulate the interactions with their cargoes. Another focus of our review is nuclear export of messenger RNA, which apparently largely relies on export mediators distinct from importin β-related factors. We discuss mechanistic aspects and the energetics of transport receptor function and describe a number of pathways in detail.

Transport between the cell nucleus and the cytoplasm.

Spinal muscular atrophy is one of the most common inherited forms of neurological disease leading to infant mortality. Patients have selective loss of lower motor neurons resulting in muscle weakness, paralysis and often death. Although patient fibroblasts have been used extensively to study spinal muscular atrophy, motor neurons have a unique anatomy and physiology which may underlie their vulnerability to the disease process. Here we report the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy. These cells expanded robustly in culture, maintained the disease genotype and generated motor neurons that showed selective deficits compared to those derived from the child’s unaffected mother. This is the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. As such, it represents a promising resource to study disease mechanisms, screen new drug compounds and develop new therapies. The inherited disease spinal muscular atrophy (SMA), one of the most common neurological disorders causing death in childhood, is caused by mutations in both copies of the SMN1 gene. Little is known about SMA pathogenesis, partly because it is unique to humans who have two versions of this gene — SMN1 and SMN2; rodents and other lab model candidates have just one. Now a new technique has been developed that creates a tool for studying SMA disease pathology at the cellular level. Skin fibroblasts from a child with SMA (and for comparison from his unaffected mother) were used to generate induced pluripotent stem (iPS) cell lines. They form neural progenitor cultures that can produce differentiated neural tissue and motor neurons that maintain the disease phenotype. The cultures also responded to drugs known to elevate the mutated protein associated with the disease. Similar iPS technology may be of value in the study of other genetic disorders such as Huntington's disease. This paper generates an iPS cell line from patients with spinal muscular atrophy, an autosomal recessive genetic disorder that is one of the most common inherited forms of neurological disease in children.

/pdf/induced-pluripotent-stem-cells-from-a-spinal-muscular-2brms3v9u9.pdf

Induced pluripotent stem cells from a spinal muscular atrophy patient

From sites of transcription in the nucleus to the outreaches of the cytoplasm, messenger RNAs are associated with RNA-binding proteins. These proteins influence pre-mRNA processing as well as the transport, localization, translation and stability of mRNAs. Recent discoveries have shown that one group of these proteins marks exon exon junctions and has a role in mRNA export. These proteins communicate crucial information to the translation machinery for the surveillance of nonsense mutations and for mRNA localization and translation.

/pdf/messenger-rna-binding-proteins-and-the-messages-they-carry-2q0ohpn695.pdf

Messenger-RNA-binding proteins and the messages they carry.

https://www.med.upenn.edu/dreyfusslab/publications/2000KataokaMC.pdf

Pre-mRNA Splicing Imprints mRNA in the Nucleus with a Novel RNA-Binding Protein that Persists in the Cytoplasm

Human transportin1 (hTRN1) is the nuclear import receptor for a group of pre-mRNA/mRNA-binding proteins (heterogeneous nuclear ribonucleoproteins [hnRNP]) represented by hnRNP A1, which shuttle continuously between the nucleus and the cytoplasm. hTRN1 interacts with the M9 region of hnRNP A1, a 38-amino-acid domain rich in Gly, Ser, and Asn, and mediates the nuclear import of M9-bearing proteins in vitro. Saccharomyces cerevisiae transportin (yTRN; also known as YBR017c or Kap104p) has been identified and cloned. To understanding the nuclear import mediated by yTRN, we searched with a yeast two-hybrid system for proteins that interact with it. In an exhaustive screen of the S. cerevisiae genome, the most frequently selected open reading frame was the nuclear mRNA-binding protein, Nab2p. We delineated a ca.-50-amino-acid region in Nab2p, termed NAB35, which specifically binds yTRN and is similar to the M9 motif. NAB35 also interacts with hTRN1 and functions as a nuclear localization signal in mammalian cells. Interestingly, yTRN can also mediate the import of NAB35-bearing proteins into mammalian nuclei in vitro. We also report on additional substrates for TRN as well as sequences of Drosophila melanogaster, Xenopus laevis, and Schizosaccharomyces pombe TRNs. Together, these findings demonstrate that both the M9 signal and the nuclear import machinery utilized by the transportin pathway are conserved in evolution.

/pdf/functional-conservation-of-the-transportin-nuclear-import-4r1dst1u0a.pdf

Functional Conservation of the Transportin Nuclear Import Pathway in Divergent Organisms

Low temperature and abscisic acid (ABA) are the two main factors that induce anthocyanin synthesis. However, their potential relationships in the regulating anthocyanin biosynthesis in tomato seedlings is still unclear. Our study revealed the involvement of the transcription factor SlAREB1 in the low-temperature response of tomato seedlings via the ABA-dependent pathway, which required a certain temperature range. Overexpression of SlAREB1 enhanced the anthocyanin-related genes expression and the anthocyanins accumulation, especially at low-temperature conditions, whereas silencing SlAREB1 remarkably reduced gene expression and anthocyanin accumulation. There is a direct interaction between SlAREB1 and the promoters of SlDFR and SlF3'5'H, which are structural genes that impact the anthocyanin biosynthesis. SlAREB1 can regulate anthocyanins through controlling SlDFR and SlF3'5'H expression. Accordingly, SlAREB1 takes charge of regulating anthocyanin biosynthesis in tomato seedlings via the ABA-dependent pathway at low temperatures.

The bZIP transcription factor SlAREB1 regulates anthocyanin biosynthesis in response to low temperature in tomato.

A novel receptor-mediated nuclear protein import pathway

The Spinal Muscular Atrophy Disease Gene Product, SMN, and Its Associated Protein SIP1 Are in a Complex with Spliceosomal snRNP Proteins

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