Altogether, our data demonstrate that mTOR functions mediated by mTORC1 are indispensable for multiple processes of NCC development including proliferation, survival, and differentiation during craniofacial morphogenesis and organogenesis, and P53hyperactivity in part accounts for the defective craniofacial development in NCC-mTOR knockout mice.
Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter genome maintenance.
Accordingly, we classified CDDP resistance by hyper-O-GlcNAcylation in lung carcinoma cells as either p53 or c-Myc dependence based on their molecular targets.
Furthermore, we found that mutp53 proteins hyper-transactivate p53-target gene CDKN1A upon glutamine deprivation, thus triggering cell cycle arrest and promoting cell survival.
Moreover, defective p53-induced hyper-recombination was associated with cell radioresistance and chromosomal stability, strongly supporting the involvement of p53 in the inhibition of hyper-recombination, which led to genetic stability and cellular function in response to DNA damage.
Given that p21 is downregulated in the majority of tumors, either by the loss of tumor suppressors like p53 or by hyperactive oncogenes such as c-myc, this finding also sheds new light on the molecular mechanisms by which p21 functions as a tumor suppressor.
Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms.
This study was designed to: (a) evaluate the induction of hyper-radiation sensitivity (HRS), a phenomenon observed at low doses of radiation (<1 Gy); (b) compare the potentiating effects of single dose radiation (2 Gy) versus the effect of low-dose fractionated radiation (LDFRT; <1 Gy) on Paclitaxel; and (c) understand the molecular mechanism of LDFRT-mediated chemo-potentiating effects, in wild-type p53 SCC-61 and p53 mutant SQ-20B head and neck squamous cell carcinoma cell lines.
This report also demonstrates that the cytoplasmic localization of p53 in neuroblastoma cells is due to its hyperactive nuclear export: p53 in these cells can be trapped in the nucleus by the export-inhibiting drug leptomycin B or by binding a p53-tetramerization domain peptide that masks the NES.
The p53 overexpression in the OLP samples may be a physiological response to the hyper-proliferative state, as revealed by the growth fraction determination.