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The role of p53 in the drug resistance phenotype of childhood neuroblastoma
Abstract/OtherAbstract :
The development of resistance to chemotherapeutic drugs is the main obstacle to the successful treatment of many
cancers, including childhood neuroblastoma, the most common solid tumour of infants. One factor that may play a
role in determining response of neuroblastoma tumours to therapeutic agents is the p53 tumour suppressor gene. A
number of previous studies have suggested that this tumour suppressor protein is inactive in neuroblastoma due to its
cytoplasmic sequestration. This thesis therefore has examined the functionality of p53 and its role in determining
drug response of neuroblastoma cells. An initial study was undertaken that characterised an unusually broad
multidrug resistance (MDR) phenotype of a neuroblastoma cell line (IMR/KAT100). The results demonstrated that
the MDR phenotype of the IMR/KAT100 cells was associated with the acquisition of mutant p53. To explore the role
of p53 in drug resistance further, p53-deficient variants in cell lines with wild-type p53 were generated by
transduction of p53-suppressive constructs encoding either shRNA or a dominant-negative p53 mutant. Analysis of
these cells indicated that: (i) in contrast to previous reports, wild-type p53 was fully functional in all neuroblastoma
lines tested, as evidenced by its activation and nuclear translocation in response to DNA damage, transactivation of
target genes and control of cell cycle checkpoints; (ii) inactivation of p53 in neuroblastoma cells resulted in
establishment of an MDR phenotype; (iii) knockdown of mutant p53 did not revert the drug resistance phenotype,
suggesting it is determined by loss of wild-type function rather than gain of mutant function; (iv) p53-dependent cell
senescence, the primary response of S-type neuroblastoma cells to DNA damage, is replaced, after p53 inactivation,
by mitotic catastrophe and subsequent apoptosis. In contrast to neuroblastoma, p53 suppression had no effect or
increased drug susceptibility in several other tumour cell types, indicating the importance of tissue context for p53-
mediated modulation of tumour cell sensitivity to treatment. Taken together, these data provide strong evidence for
p53 having a role in mediating drug resistance in neuroblastoma and suggest that p53 status may be an important
prognostic marker of treatment response in this disease.
Authors :
Xue, Chengyuan
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Publisher :  University of New South Wales. School of Women’s and Children’s Health     Type :  -     Format :  -    
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Copyright Information :, Copyright Chengyuan Xue
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Languages :  en    
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