Suppression of PMN apoptosis by hypoxia is dependent on Mcl-1 and MAPK activity

Leuenroth, Stephanie J.; Grutkoski, Patricia S.; Ayala, Alfred; Simms, Henry S.

doi:10.1067/msy.2000.107609

Cited by 60 publications

(58 citation statements)

References 17 publications

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“…The protein has sequence similarity to BCL2. Expression of the MCL1 gene is associated with inhibition of program cell death [50][51][52][53]55,56,58,60]. BAT3 is a 110 kDa protein that has an amino terminal ubiquitinlike domain, is rich in proline, and contains short tracks of polyproline, polyglycine, and charged amino acids.…”

Section: Resultsmentioning

confidence: 99%

Immediate early gene X-1 interacts with proteins that modulate apoptosis

Kumar¹,

Lutz²,

Frank³

et al. 2004

Biochemical and Biophysical Research Communications

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Immediate early gene X-1 (IEX-1) modulates apoptosis, cellular growth, mechanical strain-induced cardiac hypertrophy, and vascular intimal hyperplasia. To determine how IEX-1 alters apoptosis, we performed yeast two-hybrid studies using IEX-1 as the "bait" protein, and examined interactions between IEX-1 and proteins expressed by a human kidney cDNA expression library. We found that IEX-1 interacts with several proteins of which at least four are known to play a role in the regulation of apoptosis: (1) calcium-modulating cyclophilin ligand; (2) tumor necrosis factor-related apoptosisinducing ligand (tumor necrosis factor superfamily, member 10); (3) ML-1 myeloid cell leukemia gene encoded protein; and (4) BAT3, a gene present in the major histo-compatibility complex. Our data suggest that IEX-1 may regulate apoptosis by directly interacting with various proteins involved in the control of apoptotic pathways. KeywordsIEX-1; gly96; 1,25-Dihydroxyvitamin D; ApoptosisThe human immediate early gene X-1 (IEX-1, also known as Dif2, and murine orthologs gly96 and PRG1) plays a role in the control of apoptosis and cellular growth [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. The gene (gly96) was initially identified in mouse fibroblasts as a serum-regulated, glycosylated, immediate early gene [1]. The messenger RNA of a similar gene (p22/PRG1) is induced in rat pancreatic cells by pituitary adenylate cyclase activating peptide (PACAP) [20]. The human ortholog of gly96 and PRG1, IEX-1, was identified as an X-radiation induced in fibroblasts by Kondratyev et al. [2], and as a UV-radiation and 1α, 25-dihydroxyvitamin D 3 -regulated gene in human keratinocytes [3,4].Increased expression of IEX-1 is associated with an increase in the growth rate of keratinocytes and HeLa cells, and disruption of IEX-1 gene expression in HeLa cells and 293 cells is associated with a decrease in cellular proliferation [3,7,8,21]. IEX-1 has been shown to be induced in cardiomyocytes and vascular smooth muscle cells by mechanical stretch, and overexpression of IEX-1 in vascular smooth muscle cells protects against stretch-induced hypertrophy [9,15] IEX-1 is regulated by a variety of factors. IEX-1 expression is increased by serum, X-, and UV-irradiation, growth factors such as epidermal growth factor, inflammatory stimuli such as lipopolysaccharide and ceramide, retinoids such as all-trans-retinoic acid or cis-retinoic acid, and by over-expression of Sp1 in cells [1][2][3]6,10,11,20,[24][25][26][27][28][29][30][31]. The gene is repressed by steroid hormones such as 1α, 25-dihydroxyvitamin D 3 and by over-expression of p53 [3,4,30,32]. 1α, 25-Dihydroxyvitamin D 3 also results in a redistribution of IEX-1 from the nucleus into the peri-nuclear and cytoplasmic space. The ratio of Sp1 to p53 within the cell appears to regulate the amount of IEX-1 expression present within the cell [30]. Slight modifications of IEX-1 transcription are observed by mutating putative elements for p300, Sox, NFκB, and AP4 within the prom...

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Section: Resultsmentioning

confidence: 99%

Immediate early gene X-1 interacts with proteins that modulate apoptosis

Kumar¹,

Lutz²,

Frank³

et al. 2004

Biochemical and Biophysical Research Communications

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“…36,37 Since a significant proportion of transfected HUVECs did not manifest evidence of apoptotic changes by TUNEL assay and activated caspase-3 immunostaining after A/R in the current study, it is probable that other antiapoptotic proteins distinct from HIF-1a may also have conferred some cytoprotection against anoxic stress, as has been shown with respect to CD105 38 and Mcl-1. 39 In summary, we have employed RNAi targeting the HIF-1a gene in primary cultured HUVECs and have demonstrated the role of HIF-1a as an antiapoptotic protein in a model of anoxic stress. This study underscores the utility of using RNAi as a loss-of-function approach that is currently believed to be more efficacious, selective, and specific than antisense technologies.…”

Section: Discussionmentioning

confidence: 99%

Antiapoptotic action of hypoxia-inducible factor-1α in human endothelial cells

Liu

et al. 2004

Laboratory Investigation

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Hypoxia-inducible factor-1 (HIF-1) is the major transcription factor involved in the adaptive response to hypoxia and consists of HIF-1a and HIF-1b subunits. Indirect evidence suggests that HIF-1a may exert both proapoptotic and antiapoptotic actions in response to hypoxia. In this study, we evaluated the effects of RNA interference (RNAi) targeting HIF-1a messenger RNA (mRNA) on apoptosis in primary cultured human umbilical vascular endothelial cells (HUVECs) exposed to anoxia and reoxygenation (A/R). HUVECs were transfected with specific 21-nt small interfering RNA (siRNA) duplexes targeting HIF-1a mRNA sequences or scrambled RNA duplexes and subjected either to normoxia for 251/2 h or to anoxia for 11/2 h, and subsequently normoxia for 24 h (A/R). Control samples were subjected to A/R but not transfected. HUVECs apoptosis was evaluated by Tdt-mediated dUTP nick end-labeling (TUNEL) assay and by activated caspase-3 immunostaining and immunoblotting. The efficacy of RNAi was assessed by knockdown of HIF-1a mRNA and protein expression via in situ hybridization, real-time quantitative PCR, immunohistochemistry, and Western blotting. When compared with normoxic cultures, A/R significantly upregulated HIF-1a mRNA and protein expression in HUVECs, but did not appreciably alter the percentage of apoptotic cells. In contrast, a significantly greater proportion of HUVECs transfected with specific siRNA duplexes and exposed to A/R demonstrated evidence of apoptosis when compared with nontransfected cells. Transfection with specific siRNA duplexes knocked down HIF-1a mRNA and protein expression in A/R-treated cells by approximately 60%, whereas transfection with scrambled siRNA duplexes had no noticeable effect on HIF-1a expression. These findings strongly suggest that HIF-1a exerts an antiapoptotic role in HUVECs stressed by anoxia.

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“…82 MAP kinase mediated pathways (either MEK/ERK or p38) are also involved in the induction of MCL1 expression in other systems. [83][84][85] An additional pathway, transduced through phosphatidylinositol 3-kinase (PI3K) and AKT, is involved in the induction of MCL1 expression by GM-CSF and IL-3 in hematopoietic progenitor cells. This latter pathway acts through a transcription factor complex that contains cAMP response element binding protein (CREB).…”

Section: Mcl1 Is Regulated Through Multiple Transcriptional and Post-mentioning

confidence: 99%

MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis

2002

Leukemia

253

245

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The MCL1 gene (myeloid cell leukemia-1) was discovered serendipitously about a decade ago and proved to be a member of the emerging BCL2 gene family. Ongoing studies of this gene provide an interesting perspective on the role of the BCL2 family in transitions in cell phenotype. Specifically, gene products that influence cell viability as a major effect (eg MCL1, BCL2 and other family members) can act as key determinants in cell proliferation, differentiation and tumorigenesis. Although they do not have a direct role in proliferation/differentiation programs, these genes can either permit these programs to proceed or prevent them. Through such effects, the BCL2 family regulates the normal flow of cells through cycles of proliferation and along various pathways of differentiation. A model is presented suggesting that this is accomplished by sustaining or inhibiting viability at critical points in the cell lifecycle. These critical points represent windows of time during which cell fate transitions are effected. They can also be visualized as windows that open or close to promote or prevent continued progression along various cell fate pathways. The pattern of BCL2 family expression at these points allows for the proliferation differentiation, and continued viability of cell types that are needed, while aborting these processes for cells that are overabundant or no longer needed. The combined action of the various family members can therefore control the fate of cells, tissues and even the organism. This mechanism involving apoptosis-related genes is readily executable, and is poised to respond to external signals through the differential regulation of BCL2 family members. As such, it plays an important role in the maintenance of tissue homeostasis and function. Alterations that affect the BCL2 family impair the capacity to control the flow of cells through these critical points, and thereby 'leave the window open' for cell immortalization and cancer. Targeting this family may thus provide a means of inhibiting cancer development and inducing apoptosis in tumor cells. Leukemia (2002) 16, 444-454. DOI: 10.1038/sj/leu/2402416 Keywords: MCL1; BCL2; apoptosis; differentiation; hematopoiesis; cancer MCL1 was discovered based on increased expression during cell commitment to differentiation MCL1 was originally identified as a gene up-regulated early in the differentiation of a human myeloid leukemia cell line, ML-1. 1 These cells proliferate at an immature myeloblastic stage and undergo terminal differentiation to non-proliferative monocyte/macrophages upon exposure to phorbol esters such as 12-0-tetradecanoylphorbol 13-acetate (TPA). Commitment to differentiation occurs rapidly -within a window of several hours -upon the application of TPA to growth-arrested cells. 2 The 'commitment window' precedes phenotypic differentiation, which proceeds over the next several days. ML-1 cells that have passed through the commitment window do not difCorrespondence: RW Craig, Department of Pharmacology and Toxicology, Dartmouth Medic...

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Suppression of PMN apoptosis by hypoxia is dependent on Mcl-1 and MAPK activity

Cited by 60 publications

References 17 publications

Immediate early gene X-1 interacts with proteins that modulate apoptosis

Immediate early gene X-1 interacts with proteins that modulate apoptosis

Antiapoptotic action of hypoxia-inducible factor-1α in human endothelial cells

MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis

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