A theoretical model for p53 dynamics: Identifying optimal therapeutic strategy for its activation and stabilization

Kim, Do Hyun; Rho, Kyoohyoung; Kim, Sung Hoon

doi:10.4161/cc.8.22.10023

Cited by 18 publications

(12 citation statements)

References 67 publications

(107 reference statements)

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“…89,90 The effects of Akt and p53 on sensitivity to radiation and the induction of cellular senescence of cells are being elucidated. [91][92][93][94][95][96][97][98] In our studies, the activation of Akt-1 increased the radio resistance of MCF-7 cells, at least up to 2 grays. Some recent studies in other cancer types have shown the Akt expression can promote radioresistance.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tsupporting

confidence: 59%

Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells

et al. 2011

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Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tsupporting

confidence: 59%

Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells

et al. 2011

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“…Often some of the purported functions of p53 are overlapping and even sometimes contradictory. p53 is regulated by other transcription factors [168,169], the proteins ATM [170], MDM2 and MDMX [174-180] and other interacting proteins [181-187] and miRNAs [171-173]. Small molecule inhibitors to proteins such as MDM2 which negatively regulate p53 have been developed [56,188-190].…”

Section: Discussionmentioning

confidence: 99%

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

et al. 2011

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Escape from cellular senescence induction is a potent mechanism for chemoresistance. Cellular senescence can be induced in breast cancer cell lines by the removal of estrogen signaling with tamoxifen or by the accumulation of DNA damage induced by the chemotherapeutic drug doxorubicin. Long term culturing of the hormone-sensitive breast cancer cell line MCF-7 in doxorubicin (MCF-7/DoxR) reduced the ability of doxorubicin, but not tamoxifen, to induce senescence. Two pathways that are often upregulated in chemo- and hormonal-resistance are the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways. To determine if active Akt-1 and Raf-1 can influence drug-induced senescence, we stably introduced activated ΔAkt-1(CA) and ΔRaf-1(CA) into drug-sensitive and doxorubicin-resistant cells. Expression of a constitutively-active Raf-1 construct resulted in higher baseline senescence, indicating these cells possessed the ability to undergo oncogene-induced-senescence. Constitutive activation of the Akt pathway significantly decreased drug-induced senescence in response to doxorubicin but not tamoxifen in MCF-7 cells. However, constitutive Akt-1 activation in drug-resistant cells containing high levels of active ERK completely escaped cellular senescence induced by doxorubicin and tamoxifen. These results indicate that up regulation of the Ras/PI3K/PTEN/Akt/mTOR pathway in the presence of elevated Ras/Raf/MEK/ERK signaling together can contribute to drug-resistance by diminishing cell senescence in response to chemotherapy. Understanding how breast cancers containing certain oncogenic mutations escape cell senescence in response to chemotherapy and hormonal based therapies may provide insights into the design of more effective drug combinations for the treatment of breast cancer.

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“…Elegant models and laboratory observations have shown that cellular levels of WT-p53 and MDM2 fluctuate in an oscillatory fashion in response to stress, such as DNA damage, hypoxia, or oncogene activation, and that the numbers of pulses and the fraction of cells with oscillatory pulses increase with the strength of DNA damage. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The oscillatory kinetics and the variable amplitude of p53/MDM2 pulses over cell population may affect the measurement of MDM2 expression using immunohistochemistry (IHC), a commonly used method in clinical diagnostic and prognostic studies. If the study cohort is too small, or the cutoff is inappropriately established, the survival difference between 2 groups may not be truly reflected.…”

Section: Introductionmentioning

confidence: 99%

MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program

Xu-Monette

Møller

Tzankov

et al. 2013

Blood

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• Phenotypic and genotypic profiling of MDM2 in DLBCL.• MDM2 as a negative regulator of p53 tumor suppressor function.MDM2 is a key negative regulator of the tumor suppressor p53, however, the prognostic significance of MDM2 overexpression in diffuse large B-cell lymphoma (DLBCL) has not been defined convincingly. In a p53 genetically-defined large cohort of de novo DLBCL patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, we assessed MDM2 and p53 expression by immunohistochemistry (n 5 478), MDM2 gene amplification by fluorescence in situ hybridization (n 5 364), and a single nucleotide polymorphism in the MDM2 promoter, SNP309, by SNP genotyping assay (n 5 108). Our results show that MDM2 overexpression, unlike p53 overexpression, is not a significant prognostic factor in overall DLBCL. Both MDM2 and p53 overexpression do not predict for an adverse clinical outcome in patients with wild-type p53 but predicts for significantly poorer survival in patients with mutated p53. Variable p53 activities may ultimately determine the survival differences, as suggested by the gene expression profiling analysis. MDM2 amplification was observed in 3 of 364 (0.8%) patients with high MDM2 expression. The presence of SNP309 did not correlate with MDM2 expression and survival. This study indicates that evaluation of MDM2 and p53 expression correlating with TP53 genetic status is essential to assess their prognostic significance and is important for designing therapeutic strategies that target the MDM2-p53 interaction. (Blood. 2013;122(15):2630-2640

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A theoretical model for p53 dynamics: Identifying optimal therapeutic strategy for its activation and stabilization

Cited by 18 publications

References 67 publications

Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells

Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program

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