NIH 3T3 cells malignantly transformed by mot-2 show inactivation and cytoplasmic sequestration of the p53 protein

Wadhwa, Renu; Takano, Syuichi; Mitsui, Youji; Kaul, Sunil C.

doi:10.1038/sj.cr.7290025

Cited by 39 publications

(27 citation statements)

References 25 publications

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“…The previous works in our laboratory have been also shown an overexpression of p53 gene (data not shown). The other laboratory also demonstrated the alteration of related genes in malignant transformation of NIH 3T3 cells [16]. All there evidences indicated the alteration of expression of related genes.…”

Section: Discussionmentioning

confidence: 90%

The intracellular mechanism of alpha-fetoprotein promoting the proliferation of NIH 3T3 cells

Yang

et al. 2002

Cell Res

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Section: Discussionmentioning

confidence: 90%

The intracellular mechanism of alpha-fetoprotein promoting the proliferation of NIH 3T3 cells

Yang

et al. 2002

Cell Res

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“…2E). To ascertain whether the apoptosis associated with MDM4 overexpression is not related to inhibition of growth arrest, we analyzed cell cycle profiles following growth factor withdrawal, a condition that causes a reversible growth arrest in the G 0 phase of the cell cycle in many cell types, including fibroblasts (41,42), and is mediated by p53 activity too (41,43).…”

Section: Stable Mdm4 Overexpression Does Not Affect P53 Levels Ormentioning

confidence: 99%

MDM4 (MDMX) Overexpression Enhances Stabilization of Stress-induced p53 and Promotes Apoptosis

Mancini¹,

Gentiletti²,

D'Angelo³

et al. 2004

Journal of Biological Chemistry

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Rescue of embryonic lethality in MDM4؊/؊ mice through concomitant loss of p53 has revealed a functional partnership between the two proteins. Biochemical studies have suggested that MDM4 may act as a negative regulator of p53 levels and activity. On the other hand, MDM4 overexpression has been reported to stabilize p53 levels and to counteract MDM2-degradative activity. We have investigated the functional role of MDM4 overexpression on cell behavior. In both established and primary cells cultured under stress conditions, overexpression of MDM4 significantly increased p53-dependent cell death, in correlation with enhanced induction of the endogenous p53 protein levels. This phenomenon was associated with induced p53 transcriptional activity and increased levels of the proapoptotic protein, Bax. Further, p53 stabilization was accompanied by decreased association of the protein to its negative regulator, MDM2. These findings reveal a novel role for MDM4 by demonstrating that in non-tumor cells under stress conditions it may act as a positive regulator of p53 activity, mainly by controlling p53 levels. They also indicate a major distinction between the biological consequences of MDM4 and MDM2 overexpression.

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“…There is growing evidence that p53 sequestration in the cytoplasm may be a common mechanism of p53 inactivation. For example, both Mot-2 (Wadhwa et al 1999) and hepatitis B virus X protein (Elmore et al 1997) have been shown to physically interact with p53 and repress its transcriptional activity by sequestration in the cytoplasm. Estradiol inactivates p53 by intracellular redistribution (Molinari et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2

Sengupta¹,

Wasylyk²

2001

Genes Dev.

109

102

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The glucocorticoid receptor (GR) and the tumor supressor p53 mediate different stress responses. We have studied the mechanism of their mutual inhibition in normal endothelial cells (HUVEC) in response to hypoxia, a physiological stress, and mitomycin C, which damages DNA. Dexamethasone (Dex) stimulates the degradation of endogenous GR and p53 by the proteasome pathway in HUVEC under hypoxia and mitomycin C treatments, and also in hepatoma cells (HepG2) under normoxia. Dex inhibits the functions of p53 (apoptosis, Bax, and p21 WAF1/CIP1 expression) and GR (PEPCK and G-6-Pase expression). Endogenous p53 and GR form a ligand-dependent trimeric complex with Hdm2 in the cytoplasm. Disruption of the p53-HDM2 interaction prevents Dex-induced ubiquitylation of GR and p53. The ubiquitylation of GR requires p53, the interaction of p53 with Hdm2, and E3 ligase activity of Hdm2. These results provide a mechanistic basis for GR and p53 acting as opposing forces in the decision between cell death and survival. The development of most tumors is associated with loss of function of the tumor suppressor p53. Different physiological stress, including DNA damage and hypoxia, activate p53. p53 is a transcription factor that regulates genes involved in growth arrest and apoptosis. p53 is down-regulated by its target gene product Mdm2 (human homolog Hdm2). Mdm2 forms an autoregulatory loop with p53 by binding to its N-terminal domain, inhibiting its transcriptional activity and increasing its degradation by the ubiquitin proteasome pathway (for reviews, see Jimenez et al. 1999;Lakin and Jackson 1999;Sionov and Haupt 1999). Mdm2 is a RING finger-dependent ubiquitin protein ligase for p53 and itself (Argentini et al. 2000;Fang et al. 2000;Honda and Yasuda 2000). Mdm2 also inhibits p53 by nuclear export through a mechanism involving either the nuclear export signal (NES) of Mdm2 (Tao and Levine 1999) or the RING finger of Mdm2 and the NES of p53 (Boyd et al. 2000;Geyer et al. 2000). The NES of p53 is masked in the transcriptionally active heterodimer, but is exposed in the monomeric form of p53 ). MdmX, a Mdm2 homolog that lacks a NES, stabilizes p53 by retention in the nucleus (Jackson and Berberich 2000;Stad et al. 2000). Nuclear p53 levels can also be maintained by ARF, which blocks nucleo-cytoplasmic shuttling of Mdm2 (Sherr and Weber 2000). Most studies of p53 involve DNA damaging drugs and radiation. Much less is known about the physiological stress, hypoxia. Under hypoxic conditions, p53 is stabilized by mitochondria through a redox-dependent mechanism (Chandel et al. 2000) and by HIF-1␣ , whereas p53 induces degradation of HIF-1␣ (Ravi et al. 2000). The response to hypoxia in vivo also involves the glucocorticoid receptor (GR) (Bauer et al. 1999).GR is a member of the steroid receptor superfamily that mediates physiological processes controlled by glucocorticoids. In the unbound state GR is located in the cytoplasm bound to chaperones. Upon ligand binding the chaperones dissociate, exposing the NLS that enables GR to enter the n...

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NIH 3T3 cells malignantly transformed by mot-2 show inactivation and cytoplasmic sequestration of the p53 protein

Cited by 39 publications

References 25 publications

The intracellular mechanism of alpha-fetoprotein promoting the proliferation of NIH 3T3 cells

The intracellular mechanism of alpha-fetoprotein promoting the proliferation of NIH 3T3 cells

MDM4 (MDMX) Overexpression Enhances Stabilization of Stress-induced p53 and Promotes Apoptosis

Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2

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