Cellular senescence and chromatin structure

Cellular senescence is characterized by stable cell cycle arrest that is triggered by various forms of stress stimuli. Senescent cells show a series of morphological and physiological alterations including a flat and enlarged morphology, an increase in acidic β-galactosidase activity, chromatin condensation, and changes in gene expression pattern. These features are not observed in proliferating cells or quiescent cells in vitro. Using these senescence markers, cellular senescence has been shown to occur in benign or premalignant lesions but not in malignant lesions and to act as a tumor-suppressing mechanism in vivo. The onset and maintenance of the senescent state are regulated by two tumor suppressor proteins, p53 and Rb, which mediate senescence signals through p38 mitogen-activated protein kinase and cyclin-dependent kinase inhibitors. Alterations of chromatin structure are believed to contribute to the irreversible nature of the senescent state. Senescent cells form characteristic heterochromatin structure called senescence-associated heterochromatic foci (SAHFs), which may repress the expression of proliferation-promoting genes, such as E2F target genes. Recent studies have provided molecular insights into the structure and the mechanism of SAHF formation. In this paper, we review the role of cellular senescence in tumor suppression in vivo and the molecular mechanism of stable growth arrest in senescent cells, focusing on the special form of heterochromatin, SAHFs.     

Old enzymes, new tricks: sirtuins are NAD(+)-dependent de-acylases

Seven mammalian sirtuins are nicotinamide adenine dinucleotide (NAD)(+)-dependent deacetylases and are important modulators of energy metabolism and stress resistance. Two new studies by Du et al. (2011) and Peng et al. (2011) identify a new enzymatic activity for SIRT5, expanding the cellular repertoire of posttranslational modifications targeted by the sirtuins.     

Old dog,new tricks: Arf1 required for mitochondria homeostasis

The small GTPase Arf1 that is classically required for the budding of COPI‐coated vesicles from the Golgi membrane is now proposed to have novel and conserved roles in the morphological and functional maintenance of mitochondria: It functionally localizes to ER/mitochondria contact sites; it allows for the recruitment of a degradation machinery to mitochondria to remove toxic mitofusin/Fzo1 clusters; and it allows the extension of autophagy sequestration membranes needed for mitophagy to clear damaged mitochondria.     

Old dogs and new tricks in antimicrobial discovery

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Teaching cells new tricks

The direct conversion of one differentiated cell type into another--a process referred to as transdifferentiation--would be beneficial for producing isogenic (patient's own) cells to replace sick or damaged cells or tissue. Adult stem cells display a broader differentiation potential than anticipated and might contribute to tissues other than those in which they reside. As such, they could be worthy therapeutic agents. Recent advances in transdifferentiation involve nuclear transplantation, manipulation of cell culture conditions, induction of ectopic gene expression and uptake of molecules from cellular extracts. These approaches open the doors to new avenues for engineering isogenic replacement cells. To avoid unpredictable tissue transformation, nuclear reprogramming requires controlled and heritable epigenetic modifications. Considerable efforts remain to unravel the molecular processes underlying nuclear reprogramming and evaluate stable of the changes in reprogrammed cells.     

Old drugs, new tricks: using genetically sensitized yeast to reveal drug targets

A study in this issue of Cell illustrates the power of applying genomic approaches with model systems to characterize the biological activity of small molecules and to identify their cellular targets, which can clarify the mode of action of human therapeutics.     

Myc,Cdk2 and cellular senescence: Old players,new game

The aberrant activation of oncogenic pathways promotes tumor progression, but concomitantly elicits compensatory tumor-suppressive responses, such as apoptosis or senescence. For example, Ras induces senescence, while Myc generally triggers apoptosis. Myc is in fact viewed as an anti-senescence oncogene, as it is a potent inducer of cell proliferation and immortalization, bypasses growth-inhibitory signals, and cooperates with Ras in cellular transformation. Recent reports prompt re-evaluation of Myc-induced senescence, and of its role in tumor progression and therapy. We have shown that the cyclin-dependent kinase Cdk2, although redundant for cell cycle progression, has a unique role in suppressing a Myc-induced senescence program: Myc activation elicited expression of p16^INK4a and p21^Cip1, and caused senescence in cell lacking Cdk2, but not in Cdk2-proficient cells. Additional cellular activities have been identified that suppress Myc-induced senescence, including the Wrn helicase, Telomerase and Miz1. These senescence-suppressing activities were critical for tumor progression, as deficiency in Cdk2, telomerase or Miz1 reduced the onset of Myc-induced lymphoma in transgenic mice. Other gene products like p53, SUV39H1 or TGFß promoted senescence, which together with apoptosis contributed to tumor suppression. Paradoxically, Myc directly counteracted the very same senescence program that it potentially elicits, since it positively regulated Wrn, Telomerase and Cdk2 activity, and Cdk2 inhibition re-activated the latent senescence program in Myc expressing cells. Hence, while these molecules are instrumental to the oncogenic action of Myc, they may simultaneously constitute its Achille's heel for therapeutic development.     

Old drugs,new tricks: Emerging role of drug repurposing in the management of atopic dermatitis

Atopic dermatitis is a chronic recurring pruritic inflammatory skin disease manifested by increased pro-inflammatory mediators which lead to dry, thickened, cracked, scaly skin. The current treatment options for atopic dermatitis management comprise drawbacks and leave unmet effective clinical needs. So, the approach for repurposing existing drugs for atopic dermatitis management may potentially overcome these unmet needs. Diseases that share the common pathophysiological pathways with atopic dermatitis can serve as a foundation for the repurposing of drugs. Drugs used in the management of cancer, rheumatoid arthritis, and other immune-mediated diseases such as psoriasis are under investigation to know the potential in atopic dermatitis management by utilizing repurposing strategies for a novel therapeutic indication. This review mainly envisages the probable repurposing of drugs for the management of atopic dermatitis disease; the barriers and regulatory aspects involved in the repurposing of existing drugs.     

Regeneration and transdetermination: new tricks from old cells

In this issue of Cell, Sustar and Schubiger (2005) address a longstanding question in regeneration biology: How is pluripotency achieved during regeneration? The authors have examined the cell cycle and growth characteristics of multipotent regenerating and transdetermining Drosophila cells and come up with some surprising findings.     

Neuronal polarization: old cells can learn new tricks

Regeneration was once thought to be exclusive to young neurons. Now, a new study shows that functional and interconnected hippocampal neurons have the potential to quickly recover from losing an axon. They do so by signaling a dendrite to change its specification and replace the missing axon by rearranging the microtubule cytoskeleton.     

Lysosome-mediated processing of chromatin in senescence

Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C–negative, but strongly γ-H2AX–positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression.     

Old disease, new culprit: tumor stem cells in cancer

Eloquent studies from hematopoietic systems have provided proof that cancer arises from a tumor stem cell that possesses self-renewing properties. Until recently, it was believed that this tumor stem cell was unique to leukemic disorders; evidence now suggests that solid tumors also harbor cancer stem cells that are capable of initiating tumor growth in immunodeficient animals with as few as 10 cells. Consequently, the term "tumor-initiating cell" is now gaining favor within the field. Here, we conceptually discuss the current theories regarding tumor-initiating cells and their involvement in the development and progression of human malignancies. Special attention is given to laboratory techniques and strategies currently exploited to isolate tumor-initiating cells from larger populations, including their inherent strengths and weaknesses. The biological relevance of a tumor-initiating subpopulation is also pondered and arguments regarding their origin are presented. The therapeutic promise of targeting tumor-initiating cells is certainly eminent and we weigh the advantages of targeting this subpopulation. Lastly, the field of cancer stem cells appears to be well-placed to make significant strides over the next decade and we discuss potential obstacles that must be negotiated to achieve those objectives. The realization of these goals will undoubtedly further our understanding of this complex disease and should eventually lead to improved therapies in the not-so-distant future.     

Study of chromatin structure in ataxia-telangiectasia cells

Micrococcal nuclease was used as a probe to study chromatin structure in control and ataxia-telangiectasia cells. The rate and extent of release of acid-soluble nucleotide was similar in both cell types. Production of mono- and oligonucleosomes by micrococcal nuclease as determined by gel electrophoresis also failed to reveal differences in chromatin structure between control and ataxia-telangiectasia cells. Radiation exposure did not significantly alter the kinetics of digestion. These results indicate that there are no gross alterations in chromatin structure in ataxia-telangiectasia cells.     

tRNAs: new tricks from old dogs

tRNA biology has lately seen a revival with the discovery of tRNA cleavage products as mediators of stress responses. In this issue of The EMBO Journal, Blanco et al now report that tRNA methylation, by protecting from cleavage, is relevant for normal brain development. The versatility of tRNA is further emphasized by a recent study in Cell that uncovered differential expression of tRNAs as a means to accustom codon usage bias to the needs in proliferating versus differentiating cells.     

Nucleostemin: A latecomer with new tricks

Nucleostemin was first identified in neural stem cells and has become a focus of research in cell cycle control, tumorigenesis and cellular senescence. As the biology of nucleostemin begins to be unveiled in multiple species, an ensuing task is to resolve the apparent differences between the functions of mammalian and invertebrate nucleostemin and its homologues, an issue of pressing interest given the role of nucleostemin in stem cell self-renewal and tissue regeneration. A genome-wide search reveals that nucleostemin and its closest homologue, GNL3L, only emerge as separate genes in vertebrates and possess conserved protein sequences as evolution proceeded to the Mammalia. The invertebrate orthologue of nucleostemin and GNL3L resembles GNL3L more than it does nucleostemin in function, raising the idea that nucleostemin acquires new properties while GNL3L inherits an evolutionarily fixed role, and that the birth of nucleostemin may signify the appearance of new functional features in the vertebrate lineage.     

CaMKII: new tricks for an old dog

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a pivotal signaling molecule in both the brain and the heart. In this issue of Cell, Erickson et al. (2008) demonstrate a mechanism for CaMKII activation by reactive oxygen species that provides a direct link between kinase activation and cardiac dysfunction.