Cyclin E Restores p53 Activity in Contact-Inhibited Cells

Deffie, Abdul M.; Hao, Mingming; Luna, Roberto Montes de Oca; Hulboy, Diana L.; Lozano, Guillermina

doi:10.1128/mcb.15.7.3926

Cited by 28 publications

(22 citation statements)

References 60 publications

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“…Our unpublished data (Fung et al ) showed that p53CD( 1 -366) may have better transcriptional activation and growth suppression ability compared to p53wt in cells at the G 0 /G 1 phase of the cell cycle. This is consistent with prior observations that contact-inhibited cells lack p53 transactivation ability, which can be overcome by stimulating the cells to enter the cell cycle by overexpression of cyclin E. 21 This is due to the fact that wild -type p53 can assume two different conformations. Newly synthesized p53 in a cell exists in an inactive conformation and must be activated by posttranslational modification during S phase.…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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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“…p21 CIP1 would then prevent activation of cyclin E-CDK2 complex, and this inactivation ensures a pause in cell cycle progression allowing the cell to repair any DNA damage induced by oxidants before proceeding. Moreover, from the results presented herein and together with a recent report in the literature suggesting that cyclin E positively regulated p53 transactivation function, it is also possible to include p53 in this hypothetical scheme (64). Indeed, in O 2 -treated cells, an increased protein production was found for cyclin E but not for the other G 1 cyclins.…”

Section: Kip1supporting

confidence: 67%

Altered Regulation of G1 Cyclins in Oxidant-induced Growth Arrest of Lung Alveolar Epithelial Cells

Corroyer¹,

Maître²,

Cazals

et al. 1996

Journal of Biological Chemistry

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The alveolar surface of the lung is a major target for oxidant injury, and its repair following injury is dependent on the ability of its stem cells, the type 2 cells, to initiate proliferation. From previous studies it is likely that events located before the entry into the S phase of the cell cycle and involving several components of the insulin-like growth factor system as well as of transforming growth factor-␤ (TGF-␤) play a key role in growth regulation of oxidant-exposed type 2 epithelial cells. To gain further insights into these mechanisms, we explored the effects of O 2 exposure on G 1 cyclins and their cyclin-dependent kinases (CDKs). We documented an increased expression of these genes in O 2 -treated type 2 cells. However, despite this induction, a dramatic decrease in cyclin E-CDK2 activity, but not in cyclin D-CDK4 activity, was found. The concomitant induction of CDK inhibitory proteins (CKIs), mainly p21 CIP1 , suggests that accumulation of inactive cyclin E-CDK2 activity is due to CKI binding. We also provided evidence that the mechanisms regulating this process involved TGF-␤ as anti-TGF-␤ antibody treatment was able to reduce the oxidant-induced inhibition of cyclin E-CDK2 activity. Taken together, these results suggest that oxidants may block entry into S phase by acting on a subset of late G 1 events whose alterations are sufficient to impair the activation of cyclin E-CDK2 complexes.

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“…(Waldman et al, 1996). Since p53 responds to oncogenic stresses such as cyclin E deregulation (Deffie et al, 1995;Stewart et al, 1999), unscheduled DNA replication (Bartkova et al, 2005) or microtubule disruption (Doxsey et al, 2005), and has an essential role in the prevention of polyploidy (Di Leonardo et al, 1997;Aylon et al, 2006), it was important to verify the functionality of p53 in HCT116 Fbw7 À/À cells. We measured the level and activity of p53 by determining its own level and the levels of its target gene product, Mdm2, in Fbw7 À/À and Fbw7 þ / þ cells before and after treatment with vinblastine.…”

Section: Resultsmentioning

confidence: 99%

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

et al. 2008

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Fbw7 is a tumor suppressor that is mutated in numerous cancers. It encodes an E3 ubiquitin ligase, whose ability to decrease the levels of pivotal regulators of cell growth and proliferation underlies its tumor suppressor function. Here, we explore the consequences of Fbw7 inactivation on the outcome of chemotherapeutic treatments. When exposed to spindle toxins such as vinblastine and taxol, Fbw7-deficient cells undergo extensive mitotic slippage and endoreduplication, rendering them polyploid. A combined deregulation of several Fbw7 target proteins is required for this phenotype. Specifically, elevated expression of cyclin E and Aurora A in Fbw7-deficient cells is required for drug-induced polyploidy. However, overexpression of either cyclin E or Aurora A alone is not sufficient for drug-induced polyploidy. In addition, we demonstrate that Fbw7 deficiency limits the ability of p53 to respond to mitotic toxins but not to DNA damage. Furthermore, Fbw7 expression regulates the p53-dependent induction of genes such as Lats2 and p21 in response to vinblastine. Hence, we suggest that Fbw7 serves as a master regulator of the mitotic and tetraploidy checkpoints.

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Cyclin E Restores p53 Activity in Contact-Inhibited Cells

Cited by 28 publications

References 60 publications

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

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

Altered Regulation of G1 Cyclins in Oxidant-induced Growth Arrest of Lung Alveolar Epithelial Cells

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

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