PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Senescent fibroblasts”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 631 records · Page 35Linked to original sources
PubMed2005

AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.

AMP-Activated Protein Kinases↗
PubMed1994

Molecular biology of aging.

Aging is an extremely complex biologic phenomenon of immense importance. Currently we have only a poor and incomplete understanding of the fundamental molecular mechanisms involved. Despite numerous observations and diverse theories, no unifying or proven hypotheses have emerged. It is reasonable to conclude, however, that aging is a multifactorial process composed of both genetic and environmental components. Each physiologic system within an organism, each tissue within a system, and each cell type with a tissue appears to have its own trajectory of aging. Thus, aging must be studied as parts of a whole and understood as the sum of its parts. Cellular "clocks" exist and operate in the absence of higher-order "clocks". However, higher-order clocks are certainly in place in vivo, but their relationship to cellular clocks is not well understood. All aging changes have a cellular basis, and aging is perhaps best studied, fundamentally, at the cellular level under defined and controlled environmental conditions. Aging changes at the cellular level must be viewed, however, as components of a hierarchical, dynamic, and interacting network whose functional integrity progressively deteriorates with time. The powerful tools of molecular biology are now being applied by scientists to evaluate the leading hypotheses. The results of these studies should serve to advance our understanding of aging and to focus future research efforts. This work should provide the scientific foundation to enhance the quality of life for people suffering the failings of age.

Aging↗
PubMed1998

Markers of 'cell senescence'.

In the current literature cells that have finished their proliferative life span in vitro and have reached a terminal post-mitotic state are called senescent cells. This definition originated from the belief that the irreversible non-dividing state has a relationship with aging of the organism. Attempts have been made to find markers of the so-called senescent cell in order to detect their presence in vivo in donors of different ages. One marker which was supposed to demonstrate an increase of post-mitotic cells with aging is a marker of a long resting phase whether reversible or irreversible. Other markers suggest that the postmitotic cell does not increase with aging of the organism, that it is irrelevant for aging, that it is found in an increased number in pathology, and that the term senescent cell is a misnomer that should be used only in an operational manner.

Biomarkers↗
PubMedDate not supplied

Regulation of apoptosis resistance and ontogeny of age-dependent diseases.

Diseases of the elderly, including neurodegenerative and cardiovascular disorders and cancer, may develop through the accumulation of "hits" composed of genetic and epigenetic risk factors. The "iceberg" buildup of these hits over time may exceed the tolerance threshold of a particular tissue, thus precipitating disease. Resistance to apoptosis, a self-eliminating cellular program, is one risk factor; it is attributed to persistent survival factors, or the absence of killer factors, which form a "Yin-Yang" mechanism directing cells to either live or die. Most apoptosis-associated genes can be categorized into four groups, providing signals, signal processors, activators, or substrates for the apoptotic pathway. Senescent human fibroblasts resist apoptosis, perhaps through the lack of key G1-phase gene expressions, also necessary for apoptosis initiation; they also lack key proteolytic activity, and maintain high levels of survival factor bcl2, reflecting a triple blockage to apoptosis. Accumulations of these apoptosis-resistant fibroblasts in aging individuals may impair proper tissue function, not only as noncontributing members, but also as the seed for the buildup of further hits. With time, these cells with multiple hits and apoptosis resistance may induce susceptibility to developing age-dependent diseases.

Aging↗
PubMed2004

PML is a direct p53 target that modulates p53 effector functions.

The p53 tumor suppressor promotes cell cycle arrest or apoptosis in response to stress. Previous work suggests that the promyelocytic leukemia gene (PML) can act upstream of p53 to enhance transcription of p53 targets by recruiting p53 to nuclear bodies (NBs). We show that PML is itself a p53 target gene that also acts downstream of p53 to potentiate its antiproliferative effects. Hence, p53 is required for PML induction in response to oncogenes and DNA damaging chemotherapeutics. Furthermore, the PML gene contains p53 binding sites that confer p53 responsiveness to a heterologous reporter and can bind p53 in vitro and in vivo. Finally, cells lacking PML show a reduced propensity to undergo senescence or apoptosis in response to p53 activation, despite the induction of several p53 target genes. These results identify an additional element of PML regulation and establish PML as a mediator of p53 tumor suppressor functions.

Animals↗
PubMed2001

Osteoprogenitor cells of mature human skeletal muscle tissue: an in vitro study.

The presence of osteogenic progenitors in human skeletal muscle is suggested by the formation of ectopic bone in clinical and experimental conditions, but their direct identification has not yet been demonstrated. The aims of this study were to identify osteogenic progenitor cells in human skeletal muscle tissue and to expand and characterize them in culture. Specimens of gracilis and semitendinosus muscle were obtained from young adults and digested to separate the connective tissue and satellite cell fractions. The cells were cultured and characterized morphologically and immunohistochemically using antibodies known to be reactive with primitive osteoprogenitor cells, pericytes, intermediate filaments, and endothelial cells. Alkaline phosphatase activity and osteocalcin gene expression were also determined. In the early stages of culture, the connective tissue cells obtained were highly positive for primitive osteoprogenitor cell and for pericyte markers. Alkaline phosphatase activity was detectable at early stages of culture and rose as a function of time, whereas primitive osteoprogenitor cell markers declined and osteocalcin mRNA expression became detectable by reverse transcriptase-polymerase chain reaction (RT-PCR). It is shown that human skeletal muscle connective tissue contains osteogenic progenitor cells. Their identification as pericytes, perivascular cells with established osteogenic potential, suggests a cellular link between angiogenesis and bone formation in muscle tissue. These cells are easily cultured and expanded in vitro by standard techniques, providing an alternative source of osteogenic progenitor cells for possible cell-based therapeutic use in certain conditions.

Actins↗
PubMed2002

A single-stage mechanism controls replicative senescence through Sudden Senescence Syndrome.

Normal human cells have a finite proliferative potential in vitro. However, some DNA viral proteins, such as SV40 Tg, can alter this and extend the lifespan after which the cells enter crisis, a period when massive cell death occurs. Based on these observations, a two-stage model for cellular senescence has been proposed with a distinct function for each stage. Mortality stage 1 (M1) is hypothesized to cause cell senescence and is activated near the end of the proliferative lifespan, whereas Mortality stage 2 (M2) involves an independent mechanism that causes failure of cell division and crisis. Here, we present experimental evidence demonstrating that inhibition of the onset of Sudden Senescence Syndrome (SSS) by SV40 Tg greatly reduces the appearance of senescent cells in the culture and results in an increase in the population doublings (PD) to that of the number of cell generations (CGs). This is what causes the observed lifespan extension. Our results also provide an explanation for 'additional' telomere shortening during this 'extended' lifespan. Based on these observations, we suggest that crisis or M2 cannot be considered a 'mechanism' controlled by a specific set of genes. Our results do not support the previously proposed two-stage model and indicates SSS as the single, primary mechanism of cell senescence. Several recent findings from other laboratories that support our previously published self-recombination model of the molecular mechanisms that control SSS are discussed.

Antigens, Polyomavirus Transforming↗
PubMed2002

Limits to lifespan.

It has long-been accepted that normal somatic cells have intrinsic mechanisms that limit their proliferative lifespan. Recent work has now challenged this view by demonstrating that extrinsic factors might be determining proliferative potential.

Animals↗
PubMed1995

Exit from G0 and entry into the cell cycle of cells expressing p21Sdi1 antisense RNA.

p21Sdi1 (also known as Cip1 and Waf1), an inhibitor of DNA synthesis cloned from senescent human fibroblasts, is an inhibitor of G1 cyclin-dependent kinases (Cdks) in vitro and is transcriptionally regulated by wild-type p53. In addition, p21Sdi1 has been found to inhibit DNA replication by direct interaction with proliferating cell nuclear antigen. In this study we analyzed normal human fibroblast cells arrested in G0 and determined that an excess of p21Sdi1 was present after immunodepletion of various cyclins and Cdks, in contrast to mitogen-stimulated cells in early S phase. Expression of antisense p21Sdi1 RNA in G0-arrested cells resulted in induction of DNA synthesis as well as entry into mitosis. These results suggest that p21Sdi1 functions in G0 and early G1 and that decreased expression of the gene is necessary for cell cycle progression.

Adenovirus E1A Proteins↗
PubMed1990

Characterization of two populations of statin and the relationship of their syntheses to the state of cell proliferation.

Statin has previously been identified to be a 57-kD protein present in the nuclei of quiescent and senescent human fibroblasts, but not in their replicating counterparts (Wang, E. 1985. J. Cell Biol. 100: 545-551). In the present report we demonstrate by immunoprecipitation analysis of fractionated cellular extracts the existence of two populations of statin. The Triton X-100-soluble statin is found in replicating sparse cultures as well as in quiescent confluent cultures and quiescent serum-starved cultures of young human fibroblasts, but the Triton X-100-insoluble, nuclear envelope-localized statin is present only in the quiescent cultures. Two-dimensional gel analysis of the immunoprecipitated cellular fractions reveals that both populations of statin have an isoelectric point of 5.3. Pulse-chase experiments show that statin is synthesized as a 57-kD polypeptide and is not processed from a precursor of different molecular mass. Experiments on serum stimulation of quiescent cells show that synthesis of the Triton X-100-insoluble statin decreases rapidly during the transition from the G0 to S phase, and that this decrease is accompanied by a slower reduction in synthesis of the Triton X-100-soluble statin. These results suggest that the cellular expression of the two populations of statin may be associated with the mechanisms controlling the transition between the growing state and the quiescent state and confirm the previous finding that the Triton X-100-insoluble, nuclear envelope-localized statin could be used as a marker for cells arrested at the G0 phase of the cell cycle.

Cell Cycle Proteins↗