Identification of p53 genetic suppressor elements which confer resistance to cisplatin

Gallagher, William M.; Cairney, M.; Schott, Brigitte; Roninson, Igor B.; Brown, Raymond S.

doi:10.1038/sj.onc.1200813

Cited by 80 publications

(49 citation statements)

References 19 publications

(33 reference statements)

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“…It should be noted that many of the studies to define the impediment caused by mutant p53 have been conducted in tumor model systems. There is little doubt from several such studies that downregulation of the apoptotic process in tumor cells expressing mutant p53 is a major mechanism contributing to cisplatin resistance (Fan et al, 1994;Eliopoulos et al, 1995;Perego et al, 1996;Gallagher et al, 1997;Righetti et al, 1999). Since mutant p53 disrupts cell cycle arrest in G1, which is also the phase in which tumor cells are most sensitive to cisplatin, resistance due to loss in p53 function may be mediated in part by disruption in cell cycle checkpoints (Shah and Schwartz, 2001).…”

Section: Dysfunction Of Tumor-suppressor P53mentioning

confidence: 99%

Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003

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Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatinbased chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacologicbased mechanisms, however, are at the molecular level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.

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Section: Dysfunction Of Tumor-suppressor P53mentioning

confidence: 99%

Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003

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“…Biologically active cDNA fragments are then isolated from cells expressing the library by a positive functional selection for a specific phenotype. This concept has been used previously to identify functional regions in several genes including topoisomerase II (9), kinesin heavy chain (10,11), and p53 (12,13). Here we adjusted the screen to the conditions and principles of the TKO selection procedure (1).…”

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confidence: 99%

A functional genetic screen identifies regions at the C-terminal tail and death-domain of death-associated protein kinase that are critical for its proapoptotic activity

Raveh

Berissi

Eisenstein

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Death-associated protein kinase (DAP-kinase) is a Ca ؉2 ͞calmodulin-regulated serine͞threonine kinase with a multidomain structure that participates in apoptosis induced by a variety of signals. To identify regions in this protein that are critical for its proapoptotic activity, we performed a genetic screen on the basis of functional selection of short DAP-kinase-derived fragments that could protect cells from apoptosis by acting in a dominant-negative manner. We expressed a library of randomly fragmented DAP-kinase cDNA in HeLa cells and treated these cells with IFN-␥ to induce apoptosis. Functional cDNA fragments were recovered from cells that survived the selection, and those in the sense orientation were examined further in a secondary screen for their ability to protect cells from DAP-kinase-dependent tumor necrosis factor-␣-induced apoptosis. We isolated four biologically active peptides that mapped to the ankyrin repeats, the ''linker'' region, the death domain, and the C-terminal tail of DAP-kinase. Molecular modeling of the complete death domain provided a structural basis for the function of the death-domain-derived fragment by suggesting that the protective fragment constitutes a distinct substructure. The last fragment, spanning the C-terminal serine-rich tail, defined a new regulatory region. Ectopic expression of the tail peptide (17 amino acids) inhibited the function of DAP-kinase, whereas removal of this region from the complete protein caused enhancement of the killing activity, indicating that the C-terminal tail normally plays a negative regulatory role. Altogether, this unbiased screen highlighted functionally important regions in the protein and revealed an additional level of regulation of DAP-kinase apoptotic function that does not affect the catalytic activity. D eath-associated protein kinase (DAP-kinase) is a positive mediator of apoptosis. It was isolated by a function-based gene-cloning methodology named technical knockout (TKO) selection, which involved expression of an anti-sense cDNA library in cells, followed by selection of clones that survived in the continuous presence of an apoptotic stimulus (1). In this system, specific inhibition of DAP-kinase protein expression by anti-sense mRNA protected HeLa cells from apoptosis induced by IFN-␥ (2). Furthermore, DAP-kinase was shown to modulate cell death triggered by Fas, tumor necrosis factor ␣ (TNF-␣) (3), and detachment from extracellular matrix (4), indicating its general relevance to apoptosis.DAP-kinase is a Ca ϩ2 ͞calmodulin (CaM)-regulated serine͞ threonine kinase that is localized to the cytoskeleton, where it associates with the actin microfilament system (5). In addition to the kinase domain, which is essential for the death-promoting effects, the protein carries eight ankyrin repeats, a cytoskeleton-binding region, and a death domain. The multidomain structure of DAPkinase and its participation in a wide range of apoptotic systems imply that this protein may interact with various intracellular components to exert its act...

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“…7 Because apoptosis is a genetically programmed cellular response to environmental stresses or stimuli, mutations in apoptotic pathways and the decreased susceptibility to apoptosis have been shown to be associated with cellular resistance to chemotherapeutic drugs and radiation treatment in various human cancers including lung cancer. [25][26][27][28][29][30][31] We previously showed that exogenous expression of FUS1 in FUS1-deficient NSCLC cells might effectively inhibit tumor cell growth and induce apoptosis in vitro and in vivo. 13,15 The overexpression of FUS1 in CDDP-treated NSCLC cells may overcome the cellular resistance and enhance the cellular response to the chemotherapy by facilitating the drug-induced apoptosis and other cell dead pathways.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1

Deng

Ueda

et al. 2007

Cancer Gene Ther

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FUS1 is a novel tumor suppressor gene located in the human chromosome 3p21.3 region. We previously showed that restoration of FUS1 function in 3p21.3-deficient human non-small-cell lung cancer (NSCLC) cells significantly inhibited tumor cell growth in vitro and in vivo. In this study, we evaluated the combined effects of the tumor suppressor FUS1 and the chemotherapeutic drug cisplatin on tumor cell growth and apoptosis induction in NSCLC cells, and explored the molecular mechanism of their mutual action. Exogenous expression of FUS1 by nanoparticle-mediated gene transfer sensitized the response of NSCLC cells to cisplatin, resulting in a 4-to 6-fold increase in tumor-suppressing activity. A systemic treatment with a combination of FUS1-nanoparticles and cisplatin in a human H322 lung cancer orthotopic xenograft mouse model dramatically enhanced the therapeutic efficacy of cisplatin. We also found that the FUS1-enhanced chemosensitivity is associated with the downregulation of MDM2, accumulation of p53 and activation of the Apaf-1-dependent apoptosis pathway. Our results demonstrated an important role of FUS1 in modulating chemosensitivity of lung cancer cells, and suggested that a proper combination of molecular therapeutics such as the proapoptotic tumor suppressor FUS1 and the conventional chemotherapeutic drugs such as cisplatin may be an efficient treatment strategy for human lung cancer.

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Identification of p53 genetic suppressor elements which confer resistance to cisplatin

Cited by 80 publications

References 19 publications

Cisplatin: mode of cytotoxic action and molecular basis of resistance

Cisplatin: mode of cytotoxic action and molecular basis of resistance

A functional genetic screen identifies regions at the C-terminal tail and death-domain of death-associated protein kinase that are critical for its proapoptotic activity

Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1

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