Mimosine Arrests the Cell Cycle after Cells Enter S-Phase

Hughes, Tom; Cook, Peter R.

doi:10.1006/excr.1996.0035

Cited by 58 publications

(37 citation statements)

References 19 publications

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“…Cells were arrested in G 2 in response to p53 as described by Taylor et al (28). Briefly, mimosine (Sigma), which arrests cells reversibly at the beginning of S-phase (49), was added at a final concentration of 200 M to asynchronously growing TR9-7 cells for 48 h. The cells were released from the mimosine block and simultaneously deprived of tetracycline to induce p53-mediated arrest, mainly in G 2 (4). Recombinant adenoviruses, provided by Joseph Nevins (Duke University, Durham, NC; Ref.…”

Section: Methodsmentioning

confidence: 99%

p130/E2F4 Binds to and Represses the cdc2 Promoter in Response to p53

Taylor¹,

Schönthal²,

Galante³

et al. 2001

Journal of Biological Chemistry

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p53 represses the transcription of cdc2 and cyclin B1, causing loss of Cdc2 activity and G 2 arrest. Here we show that the region ؊22 to ؊2 of the cdc2 promoter called the R box is required for repression by p53 but not for basal promoter activity. The R box confers p53-dependent repression on heterologous promoters and binds to p130/E2F4 in response to overexpression of p53. R box-dependent repression requires p21/waf1, and overexpression of p21/waf1 also represses the cdc2 promoter. These observations suggest that p53 represses the cdc2 promoter by inducing p21/waf1, which inhibits cyclin-dependent kinase activity, enhancing the binding of p130 and E2F4, which together bind to and repress the cdc2 promoter.

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Section: Methodsmentioning

confidence: 99%

p130/E2F4 Binds to and Represses the cdc2 Promoter in Response to p53

Taylor¹,

Schönthal²,

Galante³

et al. 2001

Journal of Biological Chemistry

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“…TR9-7 cells were released from a mimosine block, which arrests them reversibly at the beginning of S phase (Hughes and Cook, 1996), and deprived of tetracycline to induce p53-mediated arrest, mainly in G2 . G2 arrest was evident 48 h after removal of mimosine in the absence of tetracycline, whereas cells incubated in the presence of tetracycline have progressed through G2 and M by this time .…”

Section: Effect Of P53 On Cak and The Cdc2/cyclin B1 Complexmentioning

confidence: 99%

Mechanisms of G2 Arrest in Response to Overexpression of p53

Taylor

DePrimo

Agarwal

et al. 1999

MBoC

168

149

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Overexpression of p53 causes G2 arrest, attributable in part to the loss of CDC2 activity. Transcription of cdc2 and cyclin B1, determined using reporter constructs driven by the two promoters, was suppressed in response to the induction of p53. Suppression requires the regions Ϫ287 to Ϫ123 of the cyclin B1 promoter and Ϫ104 to Ϫ74 of the cdc2 promoter. p53 did not affect the inhibitory phosphorylations of CDC2 at threonine 14 or tyrosine 15 or the activity of the cyclin-dependent kinase that activates CDC2 by phosphorylating it at threonine 161. Overexpression of p53 may also interfere with the accumulation of CDC2/cyclin B1 in the nucleus, required for cells to enter mitosis. Constitutive expression of cyclin B1, alone or in combination with the constitutively active CDC2 protein T14A Y15F, did not reverse p53-dependent G2 arrest. However, targeting cyclin B1 to the nucleus in cells also expressing CDC2 T14A Y15F did overcome this arrest. It is likely that several distinct pathways contribute to p53-dependent G2 arrest. INTRODUCTIONThe p53 tumor suppressor helps to protect mammals from developing neoplasia by blocking cell cycle progression or by inducing cell death in response to stress Levine, 1997;Agarwal et al., 1998b). p53-mediated arrest at the G1-S boundary prevents the replication of DNA damaged by ionizing or UV radiation or by chemical mutagens (Kastan et al., 1991;Gujuluva et al., 1994;Ceraline et al., 1998). G1 arrest depends on the ability of p53 to activate the transcription of specific genes (Dulic et al., 1994;Pietenpol et al., 1994). An important target, p21/waf1, inhibits cyclin-dependent kinases (CDKs) 1 2, 4, and 6, which are required to enter S phase (El-Deiry et al., 1993;Harper et al., 1993;Xiong et al., 1993). p53 also inhibits S-phase entry in response to damage to the mitotic spindle, preventing the rereplication of DNA (Cross et al., 1995), possibly by a transcription-independent mechanism (Notterman et al., 1998). p53 mediates G1 arrest in response to nucleotide deprivation, preventing DNA synthesis under conditions that would generate damaged DNA (Chernova et al., 1995;Linke et al., 1996). p53 also protects cells arrested within S phase by a lack of pyrimidine nucleotides, preventing the replication from unbalanced pools of deoxynucleoside triphosphates and consequent DNA damage (Agarwal et al., 1998a). A variety of stimuli that trigger p53-dependent cellular responses increase the ability of p53 to bind to DNA and induce the accumulation of the protein, attributable in large part to an increase in its stability (Maltzman and Czyzyk, 1984;Fritsche et al., 1993;Hupp et al., 1995). Responses to p53 vary in different types of cells and depend on the level of p53 expression. For example, thymocytes undergo p53-dependent apoptosis more readily than do fibroblasts (Lowe et al., 1993;Di Leonardo et al., 1994). In some cells, high levels of p53 induce apoptosis, whereas lower levels induce cell cycle arrest (Chen et al., 1996).p53 plays an important role in regulating the G2-M transition. ...

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“…commonly used as a synchronizing agent for investigating cell cycle progression in mammalian cells (3,4) and may be developed as an anticancer agent (5). However, the molecular mechanism of mimosine action on the cell cycle progression has not been elucidated.…”

mentioning

confidence: 99%

Modulation of Differentiation-related Gene 1 Expression by Cell Cycle Blocker Mimosine, Revealed by Proteomic Analysis

Dong

Arnold

Yang

et al. 2005

Molecular & Cellular Proteomics

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L-Mimosine, a plant amino acid, can reversibly block mammalian cells at late G 1 phase and has been found to affect translation of mRNAs of the cyclin-dependent kinase inhibitor p27, eIF3a (eIF3 p170), and ribonucleotide reductase M2. The effect of mimosine on the expression of these genes may be essential for the G 1 phase arrest. To determine additional genes that may be early respondents to the mimosine treatment, we performed two-dimensional gel electrophoretic analysis of [35 S]methionine-labeled cell lysates followed by identification of the altered protein spots by LC-tandem mass spectrometry. In this study, the synthesis of two protein spots (MIP42 and MIP17) was found to be enhanced by mimosine, whereas the formation of another protein spot (MSP17) was severely blocked following mimosine treatment. These protein spots, MIP42, MIP17, and MSP17, were identified to be differentiation-related gene 1 (Drg-1; also called RTP, cap43, rit42, Ndrg-1, and PROXY-1), deoxyhypusine-containing eIF5A intermediate, and mature hypusine-containing eIF5A, respectively. The effect of mimosine on eIF5A maturation was due to inhibition of deoxyhypusine hydroxylase, the enzyme catalyzing the final step of hypusine biosynthesis in eIF5A. The mimosine-induced expression of Drg-1 was mainly attributable to increased transcription likely by the c-Jun/AP-1 transcription factor. Because induction of Drg-1 is an early event after mimosine treatment and is observed before a notable reduction in the steady-state level of mature eIF5A, eIF5A does not appear to be involved in the modulation of Drg-1 expression. Molecular & Cellular Proteomics 4:993-1001, 2005.

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Mimosine Arrests the Cell Cycle after Cells Enter S-Phase

Cited by 58 publications

References 19 publications

p130/E2F4 Binds to and Represses the cdc2 Promoter in Response to p53

p130/E2F4 Binds to and Represses the cdc2 Promoter in Response to p53

Mechanisms of G2 Arrest in Response to Overexpression of p53

Modulation of Differentiation-related Gene 1 Expression by Cell Cycle Blocker Mimosine, Revealed by Proteomic Analysis

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