Regulation of p53 tumour suppressor target gene expression by the p52 NF-κB subunit (original) (raw)
Related papers
The tumour suppressor protein p53 can repress transcription of cyclin B
Nucleic Acids Research, 2000
The tumour suppressor protein p53 has functions in controlling the G 1 /S and G 2 /M transitions. Central regulators for progression from G 2 to mitosis are B-type cyclins complexed with cdc2 kinase. In mammals two cyclin B proteins are found, cyclin B1 and B2. We show that upon treatment of HepG2 cells with 5-fluorouracil or methotrexate, p53 levels increase while concentrations of cyclin B2 mRNA, measured by RT-PCR with the LightCycler system, are reduced. In DLD-1 colorectal adenocarcinoma cells (DLD-1-tet-off-p53) cyclin B1 and B2 mRNA levels drop after expression of wild-type p53 but not after induction of a DNA binding-deficient mutant of p53. Analysis of the cyclin B2 promoter reveals specific repression of this gene by p53. Transfection of wild-type p53 into SaOS-2 cells shuts off transcription from a cyclin B2 promoter-luciferase construct whereas a p53 mutant protein does not. The cyclin B2 promoter does not contain a consensus p53 binding site. Most of the p53-dependent transcriptional responsiveness resides in its 226 bp core promoter. Taken together with earlier observations on p53-dependent transcription of cyclin B1, our results suggest that one way of regulating G 2 arrest may be a reduction in cyclin B levels through p53-dependent transcriptional repression.
p53R2 Inhibits the Proliferation of Human Cancer Cells in Association with Cell-Cycle Arrest
Molecular Cancer Therapeutics, 2011
Deregulation of the expression of p53R2, a p53-inducible homologue of the R2 subunit of ribonucleotide reductase, has been found in various human cancer tissues; however, the roles p53R2 plays in cancer progression and malignancy remain controversial. In present study, we examined changes in gene expression profiles associated with p53R2 in cancer cells using the analysis of cDNA microarray. Gene set enrichment analysis (GSEA) identified the gene set regulating cell cycle progression was significantly enriched in p53R2-silencing human oropharyngeal carcinoma KB cells. Attenuation of p53R2 expression significantly reduced p21 expression and moderately increased cyclin D1 expression in both wild-type p53 cancer cells: KB, MCF-7, and mutant p53 cancer cells: PC3 and MDA-MB-231. Conversely, overexpression of p53R2-GFP resulted in an increase in the expression of p21 and decrease in the expression of cyclin D1, which correlated with reduced cell population in S-phase in vitro and suppressed growth in vivo. Furthermore, the MEK inhibitor PD98059 partially abolished modulation of p21 and cyclin D1 expression by p53R2. Moreover, under the conditions of non-stress and adriamycininduced genotoxic stress, attenuation of p53R2 in KB cells significantly increased phosphorylated H2AX, which indicates attenuation of p53R2 may enhance DNA damage induced by adriamycin. Overall, our study demonstrates that p53R2 may suppress cancer cells proliferation partially by up-regulation of p21 and down-regulation of cyclin D1; p53R2 plays critical roles not only in DNA damage repair but also in proliferation of cancer cells.
2022
TP53 codes tumor protein 53-p53 that controls the cell cycle through binding DNA directly and induces reversible cell-cycle arrest. The protein activates DNA repair genes if mutated DNA will be repaired or activates apoptotosis if the damaged DNA cannot be fixed. Therefore, p53, so-called the "guardian of the genome," promote cell survival by allowing for DNA repair. However, the tumor-suppressor function of p53 is either lost or gained through mutations in half of the human cancers. In this work, functional perturbation of the p53 mechanism is elaborated at the breast, bladder, liver, brain, lung cancers, and osteosarcoma. Mutation of wild-type p53 not only diminishes tumor suppressor activity but transforms it into an oncogenic structure. Further, malfunction of the TP53 leads accumulation of additional oncogenic mutations in the cell genome. Thus, disruption of TP53 dependent survival pathways promotes cancer progression. This oncogenic TP53 promotes cell survival, prevents cell death through apoptosis, and contributes to the proliferation and metastasis of tumor cells. The purpose of this chapter is to discuss the contribution of mutant p53 to distinct cancer types.
Molecular Cancer Therapeutics, 2008
DNA damage induces cell cycle arrest to provide time for repair and enhance cell survival. The Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) can overcome both S and G2 arrest and drive cells through a lethal mitosis. S-phase arrest induced by the topoisomerase I inhibitor SN38 results from activation of Chk1 and degradation of Cdc25A phosphatase that occurs independent of p53 status. However, p53-mediated induction of p21waf1 and repression of cyclin B prevent abrogation of S and G2 arrest, respectively. Surprisingly, incubation of MCF10A immortalized breast cells with UCN-01 fails to elevate Cdc25A protein due to p53-mediated inhibition of Cdc25A transcription. Suppression of p21waf1 in MCF10A cells overcame this transcriptional inhibition, and the S-phase-arrested cells became sensitive to UCN-01, although they now arrested in G2 as cyclin B expression remained suppressed. We also compared the response of p53 wild-type tumors to the combination of SN38 and UCN-01. In CAKI-1, U87M...
Another fork in the road—life or death decisions by the tumour suppressor p53
EMBO reports, 2013
In response to cellular stress signals, the tumour suppressor p53 accumulates and triggers a host of antineoplastic responses. For instance, DNA damage activates two main p53-dependent responses: cell cycle arrest and attendant DNA repair or apoptosis (cell death). It is broadly accepted that, in response to DNA damage, the function of p53 as a sequence-specific transcription factor is crucial for tumour suppression. The molecular determinants, however, that favour the initiation of either a p53dependent cell cycle arrest (life) or apoptotic (death) transcriptional programme remain elusive. Gaining a clear understanding of the mechanisms controlling cell fate determination by p53 could lead to the identification of molecular targets for therapy, which could selectively sensitize cancer cells to apop tosis. This review summarizes the literature addressing this important question in the field. Special emphasis is given to the role of the p53 response element, post-translational modifications and protein-protein interactions on cell fate decisions made by p53 in response to DNA damage.