Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status.

Graeber, Thomas G.; Peterson, J F; Tsai, Mitchell H.; Monica, K; Fornace, Albert J.; Giaccia, Amato J.

doi:10.1128/mcb.14.9.6264

Cited by 562 publications

(357 citation statements)

References 73 publications

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“…In response to DNA damage, like ionizing irradiation (IR) (Kastan et al, 1991), ultraviolet (UV) irradiation (Maltzman and Czyzyk, 1984;Nelson and Kastan, 1994), hypoxia (Graeber et al, 1994), and ribonucleoside triphosphate depletion (Linke et al, 1996), p53 becomes activated as a transcription factor via speci®c post-translational modi®cations. The p53 protein is phosphorylated by a wide variety of protein kinases: in its transactivation domain by casein kinase (Ck) I, DNA-PK, ATM, JNK, and MAP kinases, and at its C terminus by cyclin dependent kinases (Cdks), PKC, and Ck II (see Martinez et al, 1997;Meek, 1994 and references herein).…”

Section: Cell Cycle Check Point Control and Apoptosismentioning

confidence: 99%

Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53

Albrechtsen

Dornreiter

Grosse³

et al. 1999

Oncogene

167

121

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Section: Cell Cycle Check Point Control and Apoptosismentioning

confidence: 99%

Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53

Albrechtsen

Dornreiter

Grosse³

et al. 1999

Oncogene

167

121

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“…Indeed Reed et al (1995) have suggested that wild-type p53 may sense DNA damage directly by increased binding to DNA with strand breaks, so that DNA damage itself may lead directly to stabilisation. However p53 is also induced by non-genotoxic stress such as hypoxia and heat shock (Graeber et al, 1994). In fact cells expressing E6 show increased degradation of p53 and cannot accumulate the protein even after DNA damage, but heat or hypoxia does induce accumulation in these cells (Kessis et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding

1997

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“…Hypoxia or anoxia has been shown to induce p53 accumulation and apoptosis. 6,7 However, p53 activation by hypoxia does not appear to induce expression of classical p53 target genes such as p21, MDM2 and Bax, but can still mediate transrepression of certain genes such as a-tubulin. 8 This indicates that activation of p53 in response to hypoxia leads to a gene expression pattern that is different from that induced by p53 in response to g-irradiation, ultraviolet (UV) light and other DNA-damaging agents.…”

mentioning

confidence: 99%

Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis

et al. 2006

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p53 triggers apoptosis in response to cellular stress. We analyzed p53-dependent gene and protein expression in response to hypoxia using wild-type p53-carrying or p53 null HCT116 colon carcinoma cells. Hypoxia induced p53 protein levels and p53-dependent apoptosis in these cells. cDNA microarray analysis revealed that only a limited number of genes were regulated by p53 upon hypoxia. Most classical p53 target genes were not upregulated. However, we found that Fas/CD95 was significantly induced in response to hypoxia in a p53-dependent manner, along with several novel p53 target genes including ANXA1, DDIT3/ GADD153 (CHOP), SEL1L and SMURF1. Disruption of Fas/CD95 signalling using anti-Fas-blocking antibody or a caspase 8 inhibitor abrogated p53-induced apoptosis in response to hypoxia. We conclude that hypoxia triggers a p53-dependent gene expression pattern distinct from that induced by other stress agents and that Fas/CD95 is a critical regulator of p53-dependent apoptosis upon hypoxia. The tumor suppressor p53 regulates cellular processes such as cell cycle progression, DNA repair and apoptosis. 1 p53 is stabilized and activated in response to different types of cellular stress, for example, DNA damage, oncogenic signalling and hypoxia, and induces a biological response through transcriptional regulation of downstream target genes. The molecular mechanisms that dictate the decision of a cell to enter growth arrest or undergo apoptosis or both in response to p53 activation are only partially understood. Also, it remains unclear why different cell types display differential response to functional p53. The biological outcome of p53 activation presumably depends on several factors, including cellular context, cell type and type of stress agent. 1 It is plausible that p53 activates different specific and possibly overlapping set of target genes in response to different stress signals. Therefore, knowledge about the target genes and their regulation under different conditions is vital for the understanding of p53-mediated tumor suppression.Previous DNA microarray studies have allowed a global analysis of p53-dependent gene expression in response to p53 activation by various means. 2,3 These studies have indicated that several hundred genes are potentially regulated by p53. Moreover, in silico analysis of the human genome sequence has revealed that up to 4800 genes contain one or more potential p53 binding sites. 4,5 Thus, it is conceivable that a large number of genes are regulated by p53, although not necessarily in the same cell in response to the same stress signal. Microarray studies have so far relied on artificial cell systems for activation of p53, for example, the metallothionein promoter or expression of exogenous p53. In addition, the numbers of genes on the arrays used have been relatively low. Thus, further studies of p53-dependent gene expression based on activation of endogenous p53 in response to physiological cellular stress should provide more reliable information about p53-dependent stress respon...

show abstract

Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status.

Cited by 562 publications

References 73 publications

Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53

Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53

p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding

Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis

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