Cell cycle delay and apoptosis in response to osmotic stress

Dmitrieva, Natalia I.; Michea, Luis; Rocha, Gerson; Burg, Maurice B.

doi:10.1016/s1095-6433(01)00439-1

Cited by 76 publications

(53 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data are in agreement with those of other mammalian cell reports, which indicate that osmotic shrinkage slows cell proliferation as result of (i) blocks at the G1 and G2/M checkpoints, and (ii) S-phase prolongation (Burg, 2002;Dmitrieva et al, 2001;Michea et al, 2000). Increases in osmolality to levels >550 mOsm/kg induced apoptosis.…”

Section: Discussionsupporting

confidence: 93%

Fate of hypertonicity-stressed corneal epithelial cells depends on differential MAPK activation and p38MAPK/Na–K–2Cl cotransporter1 interaction

Capó-Aponte

Wang

Bildin

et al. 2007

Experimental Eye Research

View full text Add to dashboard Cite

The capacity of the corneal epithelium to adapt to hypertonic challenge is dependent on the ability of the cells to upregulate the expression and activity of cell membrane-associated Na-K-2Cl cotransporter1 (NKCC1). Yet, the signaling pathways that control this response during hypertonic stress are still unclear. We studied stress-induced changes in proliferation and survival capacity of SV40-immortalized human (HCEC) and rabbit (RCEC) corneal epithelial cells as a function of (i) the magnitude of the hypertonic challenge, (ii) differential changes in activation of mitogen-activated protein kinase (MAPK), and (iii) the extent of p38MAPK interaction with NKCC1. Cells were incubated in hypertonic (up to 600 mOsm) media for varying time periods up to 24 h. Phosphorylated forms of p44/42, p38, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) MAPK were immunoprecipitated from cell lysates, and the amount of each activated NKCC1-associated MAPK was evaluated by Western blot/ECL assay. DNA integrity was assessed by electrophoresis in a 2% agarose gel. Cell survival and proliferation were evaluated based on three criteria: protein content, cell count, and the MTT assay. Exposure to media of 325-350 mOsm increased proliferation of HCEC up to 75%, whereas this response was limited to <16% in RCEC. At higher osmolarities, cell proliferation decreased in both species. SAPK/JNK activity increased 150-fold in HCEC and <10-fold in RCEC, while DNA fragmentation occurred only in HCEC. Compared to HCEC, the better RCEC survival rate was associated with higher p38MAPK activity and near complete restoration of p44/42MAPK activity after the first 30 min. In both cell lines, the amount of phospho-NKCC1 that coimmunoprecipitated with phospho-p38MAPK was proportional to the magnitudes of their respective activation levels. However, no such associations occurred between amounts of phosphorylated p44/42MAPK or SAPK/JNK and phospho-NKCC1. Under isotonic conditions, with bumetanide-induced inhibition of RCEC and HCEC NKCC1 activities, p44/42MAPK activity declined by 40 and 60%, respectively. Such declines led to proportional decreases in cell proliferation. Survival of hypertonicity-stressed corneal epithelial cells depends both on p38MAPK activation capacity and the ability of p38MAPK to stimulate NKCC1 activity through protein-protein interaction. The level of NKCC1 activation affects the extent of cell volume recovery and, in turn, epithelial survival capacity.

show abstract

Section: Discussionsupporting

confidence: 93%

Fate of hypertonicity-stressed corneal epithelial cells depends on differential MAPK activation and p38MAPK/Na–K–2Cl cotransporter1 interaction

Capó-Aponte

Wang

Bildin

et al. 2007

Experimental Eye Research

View full text Add to dashboard Cite

show abstract

“…The phosphorylation of p53 underlies p53 accumulation and its subsequent prolonged protein half-life due to ubiquitination and degradation (25). The phosphorylation of p53 at Ser15 promotes the accumulation and functional activation of p53 in response to apoptotic stimuli or DNA damage (26). The current study demonstrated that p53 phosphorylation at Ser15 is increased in CCA cells treated with extracts of PEs, TCf, TCs, ACs, CL and MOs.…”

Section: Discussionsupporting

confidence: 53%

Molecular mechanisms of cholangiocarcinoma cell inhibition by medicinal plants

Leelawat

2016

Oncology Letters

View full text Add to dashboard Cite

Abstract. Cholangiocarcinoma (CCA) is one of the most common causes of cancer-associated mortality in Thailand. Certain phytochemicals have been demonstrated to modulate apoptotic signaling pathways, which may be targeted for the prevention and treatment of cancer. Therefore, the aim of the present study was to investigate the effect of specific medicinal plants on the inhibition of CCA cell proliferation, and to identify the molecular mechanisms underlying this. A WST-1 cell proliferation assay was performed using an RMCCA1 cell line, and apoptotic signaling pathways were also investigated using a PathScan Stress and Apoptosis Signaling Antibody Array Kit. The cell proliferation assay indicated that extracts from the Phyllanthus emblica fruit pulp (PEf), Phyllanthus emblica seed (PEs), Terminalia chebula fruit pulp (TCf), Terminalia chebula seed (TCs), Areca catechu seed (ACs), Curcuma longa (CL) and Moringa oleifera seed (MOs) exerted anti-proliferative activity in RMCCA1 cells. In addition, the PathScan assay revealed that certain pro-apoptotic molecules, including caspase-3, poly (ADP-ribose) polymerase, checkpoint kinase 2 and tumor protein 53, exhibited increased activity in RMCCA1 cells treated with the aforementioned selected plant extracts, with the exception of PEf. The mitogen-activated protein kinase (MAPK) pathways (including ERK1/2 and p38 MAPK) expression level was significantly increased in RMCCA1 cells pre-treated with extracts of PEs, TCf, CL and MOs. The activation of protein kinase B (Akt) was significantly demonstrated in RMCCA1 cells pre-treated with extracts of TCf, ACs and MOs. In summary, the present study demonstrated that extracts of PEs, TCf, TCs, ACs, CL and MOs exhibited anti-proliferative effects in CCA cells by inducing pro-apoptotic signals and modulating signal transduction molecules. Further studies in vivo are required to demonstrate the potential applications of specific plant extracts for the treatment of human cancer.

show abstract

“…It has been shown that exposure of kidney cells to acute hypertonic stress (600 mosM) causes DNA double-strand breaks (22), and widespread DNA strand breaks were also detected in the kidney inner medulla in vivo (30). This is concomitant with the induction of p53 and cell cycle delay (24,31,32). In lens fiber cells of the OREBPdn Tg mice, DNA damage was accompanied by the activation of the DNA damage checkpoint pathway, as evidenced by the phosphorylation of Chk2.…”

Section: Discussionmentioning

confidence: 96%

Transgenic Mice Expressing Dominant-negative Osmotic-response Element-binding Protein (OREBP) in Lens Exhibit Fiber Cell Elongation Defect Associated with Increased DNA Breaks

Wang

Yang

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Osmotic-response element-binding protein (OREBP), also known as TonEBP or NFAT5, is thought to be responsible for the induction of osmolyte-accumulating genes when cells are under hypertonic stress. Recent studies suggest that OREBP also plays a role in water reabsorption in the kidney, T-cell proliferation, and embryonic development. We developed transgenic mice that express the dominant-negative OREBP (OREBPdn) specifically in the lens because our earlier studies showed that it is particularly sensitive to osmotic stress. The transgenic mice developed nuclear cataract soon after birth, suggesting defects in lens development. The developing transgenic lenses showed incomplete elongation of fiber cells and formation of vacuoles. This is accompanied by evidence of DNA strand breaks, activation of p53, and induction of checkpoint kinase, suggesting that the developing fiber cells lacking OREBP are in a similar physiological state as cells experiencing hypertonic stress. These results indicate that OREBP-mediated accumulation of osmolytes is essential during elongation of the lens fiber cells.The osmotic-response element-binding protein (OREBP), 1 also known as TonEBP or NFAT5, is a member of the NFAT transcription factor family characterized by the presence of the Rel homology DNA-binding domain (1, 2). Unlike other members in the NFAT family that are responsible for effective immune response, OREBP/TonEBP is primarily involved in the genetic program that is essential for cellular survival in response to hypertonic stress (3). Through binding to the osmoticresponse element (ORE) or the tonicity-responsive enhancer (TonE), OREBP/TonEBP mediates the hypertonic induction of a set of osmoprotective genes including aldose reductase, betaine/␥-aminobutyric acid transporter, and sodium-myo-inositol cotransporter, resulting in the cellular accumulation of sorbitol, betaine, and myo-inositol, respectively (4 -6). It is well established that these small molecule organic osmolytes are able to replace excess intracellular electrolytes that are otherwise deleterious to normal cell functions (7). This adaptive mechanism is particularly important in the kidney medulla, where cells are constantly exposed to steep osmotic gradient due to the urine concentration mechanism. Besides, OREBP is also responsible for the hypertonic induction of HSP70 (8), a molecular chaperone that plays a vital role in cellular adaptation to osmotic stress (9).There are growing evidences suggesting that OREBP is involved in diverse cellular responses in addition to osmoprotection. In Drosophila, OREBP orthologue MESR1 was identified as a modifier of RAS1 signaling involved in eye development (10). On the other hand, OREBP was also implicated in cancer cell migration and cancer metastasis (11). In mouse embryo, OREBP is expressed in most developing tissues including brain, eye, heart, kidney, colon, and muscle. Since these developing organs are not expected to experience hypertonic stress, the physiological role of OREBP in these tissues remains elusive ...

show abstract

Cell cycle delay and apoptosis in response to osmotic stress

Cited by 76 publications

References 38 publications

Fate of hypertonicity-stressed corneal epithelial cells depends on differential MAPK activation and p38MAPK/Na–K–2Cl cotransporter1 interaction

Fate of hypertonicity-stressed corneal epithelial cells depends on differential MAPK activation and p38MAPK/Na–K–2Cl cotransporter1 interaction

Molecular mechanisms of cholangiocarcinoma cell inhibition by medicinal plants

Transgenic Mice Expressing Dominant-negative Osmotic-response Element-binding Protein (OREBP) in Lens Exhibit Fiber Cell Elongation Defect Associated with Increased DNA Breaks

Contact Info

Product

Resources

About