p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

Zerp, S.F.; Elsas, Andrea van; Peltenburg, L. T. C.; Schrier, Peter I.

doi:10.1038/sj.bjc.6690147

Cited by 82 publications

(63 citation statements)

References 22 publications

(33 reference statements)

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“…Interestingly, the tumour suppressor gene for TP53 is mutated in a high proportion of cancers, but very few melanomas 70 . The inactivation of p53 through the deletion or mutation of TP53 leads to a reduced level of apoptotic cell death, providing the cell with increased survival potential.…”

Section: Chemoresistance and Treatment In Malignant Melanomamentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Section: Chemoresistance and Treatment In Malignant Melanomamentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…Interestingly, a recent report has shown that a small percent of wild type p53 localizes to the mitochondria in several types of human cancer cell lines that have been induced into apoptosis by chemotherapy agents and growth factor withdrawal (Marchenko et al, 2000). The frequency of p53 mutations in human melanomas are lower than in most other cancer types (10 ± 30% vs 50%, respectively) (Albino et al, 1994;Zerp et al, 1999) and the role of p53 in the induction of apoptosis in melanoma is still incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Formation of nuclear Bax/p53 complexes is associated with chemotherapy induced apoptosis

2000

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Mechanisms by which chemotherapeutic agents induce apoptosis are not completely understood. Current knowledge of the actual pharmacologic e ects of chemotherapy and their biochemical mechanisms are better understood than the downstream events, which initiate the apoptotic cascade. The chemotherapeutic agent cisplatin causes DNA damage and can induce apoptosis in several types of human cancers. We found the formation of previously unreported nuclear complexes between the tumor suppressor protein p53 and the proapoptotic protein Bax, in human melanoma cell lines induced into apoptosis following cisplatin exposure. These detergent resistant complexes were detected: after wild type (wt) p53 and Bax increased in the nucleus; at the same time when active cytoplasmic apoptosis related protease, caspase 3/CPP32 appeared; and prior to the detection of apoptotic DNA fragmentation. Three channel¯uorescence laser scanning confocal image microscopy revealed that the nuclear Bax/p53 complexes remained in the nucleus and localized proximal to DNA fragmentation sites as assayed by TUNEL after cisplatin exposure. Two human melanoma cell lines, expressing wt p53, were induced into apoptosis after cisplatin exposure, however they di ered in the timing of this induction. In both cell lines the formation of nuclear Bax/p53 coimmunoprecipitable complexes correlated with the timing of the induction of apoptosis. The degree of apoptosis induced by di erent concentrations of cisplatin correlated with the amount of nuclear Bax/p53 complexes. The coimmunoprecipitation of Bax and p53 was found regardless of the antibodies tested and was speci®c since Bcl-x L /p53 complexes were not detected. Additionally, the human prostate cancer cell line, LNCaP, also formed nuclear Bax/p53 complexes only after apoptosis was induced by paclitaxel. Oncogene (2000) 19, 6216 ± 6228.

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“…Arginine at codon 209 was found mutated in 69 tumors, including five tumors that harbor the exact arginine-to-lysine replacement. [35][36][37][38][39] Multiple alignment performed among 44 species indicated that the amino acid at position 209 in humans is not a Spalax-unique change. Actually, there is a vast variability at this nonconserved region, with 10 different amino acid possibilities among the species examined.…”

Section: Spalax P53 Biologymentioning

confidence: 99%

p53: A Key Player in Tumoral and Evolutionary Adaptation: A Lesson from the Israeli Blind Subterranean Mole Rat

Avivi¹,

Ashur‐Fabian²,

Amariglio³

et al. 2005

Cell Cycle

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ABSTRACTp53 is a transcription factor involved in maintaining genomic integrity by regulating genes involved in cell cycle arrest, DNA repair, and programmed cell death. Various post transcriptional modifications result in activated p53 with varying binding affinity to its targets. The other members of the p53 family (p63, p73) and associated proteins also contribute to the specificity of gene activation resulting in the final cell responses. p53 is commonly mutated in human cancer and is activated by diverse cellular events, including hypoxia. Many sources of genetic diversity, including random or stress-related mutagenesis, affect normal species evolution. The blind subterranean mole rat lives in sealed underground tunnels, subjected to routine hypoxia due to abrupt and sharp changes in O2 supply. We cloned the mole rat's p53 gene and identified two amino acid substitutions in its binding domain, in the same positions that are mutated in cancer. These substitutions lead to increased p53 activation of DNA-repair elements and reduced activation of apoptotic genes. We propose that sequence-specific changes in the mole rat's p53 gene provide an example of how transcription factors that regulate many genes can also account for rapid and broad phenotypic diversity by altering the binding affinity to individual target genes.

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p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

Cited by 82 publications

References 22 publications

Role of the pro-survival molecule Bfl-1 in melanoma

Role of the pro-survival molecule Bfl-1 in melanoma

Formation of nuclear Bax/p53 complexes is associated with chemotherapy induced apoptosis

p53: A Key Player in Tumoral and Evolutionary Adaptation: A Lesson from the Israeli Blind Subterranean Mole Rat

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