Evidence for a p53‐independent pathway for upregulation of <i>SDI1/CIP1/WAF1/P21</i> RNA in human cells

Johnson, M. B.; Dimitrov, Diana; Vojta, Patrick J.; Barrett, J. Carl; Noda, Asao; Pereira‐Smith, Olivia M.; Smith, James R.

doi:10.1002/mc.2940110202

Cited by 134 publications

(86 citation statements)

References 21 publications

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“…Similarly, no p21 WAF1/CIP1 response was detected in the p53 null MDA-MB157 cells (Figure 1a). The P21 WAF1/CIP1 overexpression following ionizing radiation was reported to be speci®cally p53-dependent (Johnson et al, 1994). We compared, p53 and p21 WAF1/CIP1 response to ionizing radiation and adriamycin treatment in breast adenocarcinoma cell lines.…”

Section: P53 Response To Adriamycin Treatment In Breast Cell Linesmentioning

confidence: 99%

“…Some of these signals include serum stimulation, treatment with growth factors, cytokines and di erentiation-inducing agents. Furthermore, although the expression of P21 WAF1/CIP1 in response to genotoxic treatment is predominantly under p53 control, a p53-independent induction of P21 WAF1/CIP1 expression was also reported following treatment with di erent genotoxic drugs (Johnson et al, 1994;Michieli et al, 1994). The speci®city of the P21 WAF1/CIP1 response appears to be dependent on the type and the dose of the drug.…”

Section: Introductionmentioning

confidence: 99%

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p21WAF1/CIP1 response to genotoxic agents in wild-type TP53 expressing breast primary tumours

et al. 1997

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Functional inactivation of the wild-type p53 protein has been described in di erent human cancers. Since a signi®cant proportion of breast tumours express wildtype TP53, the p53 antiproliferative activity could be inactivated in transformed mammary epithelial cells by a mechanism independent on structural alteration of the gene. To test this hypothesis, we analysed the p53 activity in primary breast tumour cells. As a preliminary study, we demonstrated in breast adenocarcinoma cell lines that the nuclear accumulation of the inhibitor of cyclin dependent kinase p21 WAF1/CIP1 , in response to adriamycin treatment, speci®cally re¯ected the activity of a functional wild-type p53 protein. Then, we used this strategy to study the p53 activity in 23 primary breast tumours. p21 WAF1/CIP1 accumulation was detected in all tumours expressing wild-type TP53. In contrast, no p21 WAF1/CIP1 response was detected in cells harboring a mutant TP53 gene. This report is the ®rst functional study of p53 in primary breast tumours. The results demonstrate that TP53 mutation represents the only common mechanism leading to an irreversible inactivation of p53 functions in this cancer type.

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Section: P53 Response To Adriamycin Treatment In Breast Cell Linesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

p21WAF1/CIP1 response to genotoxic agents in wild-type TP53 expressing breast primary tumours

et al. 1997

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“…The mechanism by which p21 Cip-1/WAF1 is induced in response to irradiation of cells has been proposed to be via the function of p53 which is able to sense DNA damage, and not by MAP kinase signaling. This data would appear to preclude signaling via the MAP kinase cascade as a player in the radiationmediated induction of p21 Cip-1 (Missero et al, 1996;Macloed et al, 1995;Liu et al, 1996;Deng et al, 1995;Van den Heuvel and Harlow, 1993;Lees et al, 1993;Brugarolas et al, 1995;Freemerman et al, 1997;Akiyarna et al, 1997;Mothersill et al, 1995;Bernhard et al, 1995;Muschel et al, 1997;Johnson et al, 1994;Michieli et al, 1994;Poon et al, 1996). These studies were initiated to test if radiationinduced activation of the MAP kinase cascade is cytoprotective against radiation-induced activation of the SAP kinase cascade in A431 squamous carcinoma cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells

et al. 1998

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The molecular mechanism(s) by which tumor cells survive after exposure to ionizing radiation are not fully understood. Exposure of A431 cells to low doses of radiation (1 Gy) caused prolonged activations of the mitogen activated protein (MAP) kinase and stress activated protein (SAP) kinase pathways, and induced p21 Cip-1/WAF1 via a MAP kinase dependent mechanism. In contrast, higher doses of radiation (6 Gy) caused a much weaker activation of the MAP kinase cascade, but a similar degree of SAP kinase cascade activation. In the presence of MAP kinase blockade by the speci®c MEK1 inhibitor (PD98059) the basal activity of the SAP kinase pathway was enhanced twofold, and the ability of a 1 Gy radiation exposure to activate the SAP kinase pathway was increased *sixfold 60 min after irradiation. In the presence of MAP kinase blockade by PD98059 the ability of a single 1 Gy exposure to cause double stranded DNA breaks (TUNEL assay) was enhanced at least threefold over the following 24 ± 48 h. The increase in DNA damage within 48 h was also mirrored by a similar decrease in A431 cell growth as judged by MTT assays over the next 4 ± 8 days following radiation exposure. This report demonstrates that the MAP kinase cascade is a key cytoprotective pathway in A431 human squamous carcinoma cells which is activated in response to clinically used doses of ionizng radiation. Inhibition of this pathway potentiates the ability of low dose radiation exposure to induce cell death in vitro.

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“…On the other hand, it also is possible that p53-independent pathways contribute to the ability of HPV-positive cancer cells to induce cell cycle arrest or apoptosis following DNA damage. For example, the growth inhibitory p21 WAF1 gene can also be activated by genotoxic agents via p53-independent pathways (Johnson et al, 1994;Loignon et al, 1997;Butz et al, 1998). Thus, although HPV-positive cancer cells can exhibit at least some features of an intact cellular response to genotoxic stress, the underlying mechanisms are still unresolved and it is not yet clear whether HPV-positive cancer cells contain enough functional p53 to transactivate a physiological target gene following DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Induction of the p53-target gene GADD45 in HPV-positive cancer cells

et al. 1999

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The E6 oncoprotein of human papillomaviruses (HPVs) has the potential to functionally antagonize p53. In several experimental model systems, ectopic expression of E6 can block the genotoxic induction of the growth inhibitory p53 target gene gadd45, suggesting that the inactivation of this pathway may play a major role for HPV-associated cell transformation. Here, we investigated whether this re¯ects the regulation of gadd45 expression in carcinoma-derived HPV-positive cells. We found that the gadd45 gene is e ciently induced by mitomycin C, cisplatin, and UV irradiation in a series of HPV-positive cervical cancer cell lines. Moreover, clear induction of gadd45 gene expression was also observed following treatment with g-irradiation, a pathway that is strictly dependent on functional p53. This contrasted with ®ndings in human foreskin keratinocytes experimentally immortalized by expressing the HPV16 E6, E7, or E6/E7 oncogenes from the heterologous CMV promoter, where expression of the E6 gene was linked to a lack of gadd45 induction following g-irradiation.These results indicate (1) that the tumorigenic phenotype of HPV-positive cancer cells is not linked to an inability to induce the gadd45 gene following DNA damage, (2) that experimental model systems in which the E6 gene is expressed ectopically and/or in a di erent cellular context do not necessarily re¯ect the regulation of p53-associated pathways in HPV-positive cancer cells and (3) that a pathway strictly depending on functional p53 is inducible in HPV-positive cancer cells, providing direct evidence that the endogenous p53 protein in these cells is competent to activate a cellular target gene, despite coexpression of the viral E6 oncogene.

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Evidence for a p53‐independent pathway for upregulation of SDI1/CIP1/WAF1/P21 RNA in human cells

Cited by 134 publications

References 21 publications

p21WAF1/CIP1 response to genotoxic agents in wild-type TP53 expressing breast primary tumours

p21WAF1/CIP1 response to genotoxic agents in wild-type TP53 expressing breast primary tumours

Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells

Induction of the p53-target gene GADD45 in HPV-positive cancer cells

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