WAF1, a potential mediator of p53 tumor suppression

El‐Deiry, Wafik S.; Tokino, Takashi; Velculescu, Victor E.; Levy, Daniel B.; Parsons, Ramon; Trent, Jeffrey M.; Lin, David Pei-Cheng; Mercer, W E; Kinzler, Kenneth W.; Vogelstein, Bert

doi:10.1016/0092-8674(93)90500-p

Cited by 7,717 publications

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“…We were unable to detect p15 INK4B in TGF-b1-treated IEC-6 cells, although we can easily detect this inhibitor in mink lung epithelial cells. We were able to detect expression of two universal Cdk inhibitors, p21 (Harper et al, 1993;El-Deiry et al, 1993;Xiong et al, 1993) and p27 (Polyak et al, 1994; Figure 2 The abundance of cyclin D1/Cdk4 complexes, Cdk4-associated kinase activity and cyclin D3/p27 in TGF-b1-treated cells. Serum-starved, quiescent IEC-6 cultures were stimulated with 5% FBS with vehicle (7) or TGF-b1 (+).…”

Section: Resultsmentioning

confidence: 99%

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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Transforming growth factor-beta 1 (TGF-b1) arrests intestinal epithelial cells (RIE-1 and IEC-6) in the G1 phase of the cell cycle and inhibits cyclin D1 expression. This report describes experiments designed to elucidate the mechanism of cyclin D1 inhibition and to determine whether inhibition of cyclin D1 expression is the cause, rather than the result, of TGF-b1-mediated cell cycle arrest. TGF-b1 inhibition of IEC-6 cell proliferation was associated with a decrease in the abundance of cyclin D1/Cdk4 complexes and a corresponding decrease in Cdk4-dependent phosphorylation of the retinoblastoma protein. Metabolic labeling studies indicated that TGFb1 inhibited cyclin D1 synthesis without altering the rate of cyclin D1 protein degradation. Cyclin D1 antisense oligonucleotides blocked serum-stimulated induction of cyclin D1 and DNA synthesis, whereas cyclin D1 sense oligonucleotides had no e ect. RIE-1 cells were engineered to overexpress human cyclin D1 under the control of a tetracycline-repressible promoter. These cells entered S phase in the presence of TGF-b1 only when human cyclin D1 was derepressed by the withdrawal of tetracycline. These data indicate that TGF-b1 inhibits the synthesis of cyclin D1 in gut epithelial cells and that this inhibition is the cause, rather than the result, of TGF-b1-mediated arrest of intestinal epithelial cell proliferation.

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Section: Resultsmentioning

confidence: 99%

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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“…The p53 levels were normalized to the total protein content measured by the BCA protein assay (Pierce, Rockford, IL ). For in vivo expression, athymic nude mice were exposed to PEI -p53 aerosol, sacrificed at various time points (24,48,72, and 96 hours ) later, and the lungs harvested and weighed. The lungs were homogenized in 1 mL of ice -cold cell lysis buffer ( 20 mM Tris, 0.5 mM EDTA, 1% Nonidet P40, 0.05% sodium dodecyl sulfate (SDS ), 1 mM PMSF, 1 mg /mL pepstatin, 2 mg /mL leupeptin ) using a Wig -L -Bug bead homogenizer (Crescent, Lyons, IL).…”

Section: Development Of Lung Micrometastasesmentioning

confidence: 99%

“…p53 expression in lung was analyzed by ELISA at different time points ( 24,48,72, and 96 hours ) after aerosol delivery of the PEI -p53 complexes to the mice ( Fig 2). Aerosol delivery of PEI -p53 complexes lead to about a 3-fold increase in the levels of p53 detected in the lung tissue compared to that detected in the lungs of naive mice.…”

Section: Transfection Of Saos -Lm6 Cells In Vitro By Pei -P53 Complexesmentioning

confidence: 99%

Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI– p53 complexes

et al. 2001

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Lung metastases are a frequent complication of osteosarcoma and a treatment that would reduce the severity of this complication would be of great benefit to patients. We have used a formulation consisting of polyethyleneimine ( PEI ) and a p53 gene administered in aerosol to treat established lung micrometastases as a model of human osteosarcoma in nude mice. The SAOS -LM6 cell line, a metastatic derivative of the p53 null SAOS -2 line, expresses high levels of p53 protein after in vitro transfection with PEI -p53 complexes as determined by ELISA, and transfection with both p53wt and the p53 variant, p53 -CD( 1 -366 ) in vitro, results in a marked inhibition of SAOS -LM6 cell proliferation. Aerosol delivery of plasmid DNA containing either the p53 gene or a p53 -CD( 1 -366 ) variant gene formulated with PEI to mice resulted in highly significant reductions in the numbers and size of tumors ( P < .001 ), the total number of tumor foci in the lungs ( P < .001 ) and the size of individual tumor nodules in treated animals compared to untreated, PEI only -treated and PEI -CAT -treated control animals. The different tissues examined did not reveal any signs of toxicity or inflammation after repeated exposure to PEI -DNA. The aerosol delivery of PEI -based formulations of p53 or synthetic p53 variant genes represents a promising new strategy for the treatment of established human osteosarcoma lung metastases. The noninvasive nature of aerosol delivery coupled with low toxicity also make this therapeutic approach potentially appropriate for combination therapy with either radio -or chemotherapy.

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“…A number of cellular genes has been found to be induced by p53. Among these are p21 (el-Deiry et al, 1993), GADD45 (Kastan et al, 1992), BAX (Miyashita et al, 1994), MDM2 (Wu et al, 1993), BTG2 (Rouault et al, 1996), PIGs ), 14-3-3s (Hermeking et al, 1997, IGFBP3 (Buckbinder et al, 1995), PI(3)K regulatory subunit p85 (Yin et al, 1998), KILLER/DR5 , and TAP I (Zhu et al, 1999). p21, 14-3-3s, GADD45, and BTG2 have been shown to be capable of mediating p53-dependent cell cycle arrest (Chen et al, 1996;elDeiry et al, 1993;Hermeking et al, 1997;Rouault et al, 1996;Wang et al, 1999) while BAX, p85, IGFBP3, KILLER/DR5 and PIGs may mediate apoptosis (Buckbinder et al, 1995;Miyashita et al, 1994;Polyak et al, 1997;Wu et al, 1997;Yin et al, 1998).…”

mentioning

confidence: 99%