Transcriptional activation of the human proliferating-cell nuclear antigen promoter by p53.

Morris, Gilbert F.; Bischoff, James R.; Mathews, Michael B.

doi:10.1073/pnas.93.2.895

Cited by 115 publications

(80 citation statements)

References 60 publications

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“…JI-38 strongly suppressed the expression of p53, in accord with previous results which reported downregulation of this protein by GHRH (11). Tumor suppressor protein p53, which suppresses the promoter of PCNA (29), plays a crucial role in cancer, since the loss of its functionality occurs during the development of most tumor types (30). PCNA also plays a critical role in regulating the stability of p53, since its inactivation of PCNA can induce the stabilization of p53 (31).…”

Section: Discussionsupporting

confidence: 79%

Effects of growth hormone-releasing hormone and its agonistic and antagonistic analogs in cancer and non-cancerous cell lines

Barabutis

Siejka

2010

Int J Oncol

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Abstract. The neuropeptide growth hormone-releasing hormone (GHRH) is secreted by the hypothalamus and upon the binding to the receptors for GHRH on the pituitary gland regulates the release of growth hormone. Substantial evidence indicate that GHRH, in addition to its physiological role as a hypophysiotrophic hormone, acts as a growth factor in diverse tissues and various tumors. In this study we evaluated the expression of GHRH and its receptors in a variety of cancer and non-cancerous cell lines and studied the effect of GHRH antagonists and agonists on the proliferative cell nuclear antigen, cyclin D3, tumor suppressor protein p53 and carboxyl-terminal-binding protein (CtBP1). Our findings show that GHRH agonist JI-38 downregulates wt-p53 and upregulates the expression of PCNA. GHRH also upregulates CtBP1 protein expression and its antagonists downregulate it in LNCaP prostate cancer cells. Furthermore, GHRH and its agonist JI-38 upregulates the expression of the proliferative markers cyclin D3 and PCNA in A549 non-small cell lung carcinoma and GHRH antagonist MZ-5-156 downregulates it. Our results support previous findings on the mitogenic role of GHRH in cancers and underline the importance of GHRH antagonists as anticancer agents.

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Section: Discussionsupporting

confidence: 79%

Effects of growth hormone-releasing hormone and its agonistic and antagonistic analogs in cancer and non-cancerous cell lines

Barabutis

Siejka

2010

Int J Oncol

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“…These findings support the results previously reported 1,23 and indicate that the G2 delay had been overridden and cells had accumulated at G0/G1. p53 has been implicated not only at the G1 checkpoint, but also in later phases of the cell cycle, such as PCNA-dependent DNA replication 27 and the mitotic checkpoint, 28 both of which are essential for the maintenance of diploidy. As we have previously shown, LCL286A is characterized by the accumulation of a DNA content exceeding 4C at 72 and 144 h after X-IR.…”

Section: Caffeine Induces Cell Cycle Progression In Cells With P53 Mumentioning

confidence: 99%

DNA damage-associated cell cycle and cell death control is differentially modulated by caffeine in clones with p53 mutations

Takagi

Shigeta

Asada³

et al. 1999

Leukemia

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Caffeine is known to potentiate the cytotoxic effects of DNA damaging agents and increases the sensitivity of p53-deficient cells to X-irradiation (X-IR). We have analyzed the cell cycle and cell death control after X-IR in the absence or presence of caffeine in hematological cell lines with various configurations of the p53 gene; EBV-immortalized lymphoblastoid cells with heterozygous p53 mutation (wt/mt), human leukemia cell lines HL60 and KOPM28 with no and mutant p53 expression, respectively. These cell lines display an impaired G0/G1 checkpoint and G2 delay following X-IR, and resistance to apoptosis, which are in accordance with findings previously reported. When irradiated in combination with caffeine, all these cell lines overrode the G2 delay and accumulated at G0/G1. The cell cycle modifications in these cell lines correlated with the increase in radiation-induced p34Cdc2 kinase activity by caffeine. These cell cycle control modifications by caffeine, however, were not associated with enhancement of radiation-induced apoptosis or reduction of clonogenic growth activity in these cell lines. These results suggest that the cytocidal effect of caffeine may need to be verified independently of its cell cycle regulatory activities at least in some cases with p53 mutation.

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“…The list of genes that possess these DNA sites is rapidly increasing and includes: waf-J/cip-J (El-Deiry et al, 1993), gadd45 (Kastan et al, 1992 and references therein), MDM2 (Zauberman et al, 1995a), bax (Miyashita and Reed, 1995), cyclin G (Zauberman et al, 1995b), insulin-like growth factor binding protein 3 (IGF-BP3) (Buckbinder et al, 1995), epidermal growth factor receptor (EGF-r) (Deb et al, 1994), transforming growth factor-a (TGF-a) (Shin et al, 1995), proliferating cell nuclear antigen (PCNA) (Morris et al, 1996), thrombospondin-J (Dameron et al, 1994), fas/APO-1 (Owen-Schaub et al, 1995), Rb (Osifchin et al, 1994), cyclin D , ras (Spandidos et al, 1995;Zhang et al, 1995) and p53 itself (Deffie et al, 1993).…”

mentioning

confidence: 99%

Effects of p53 mutants derived from lung carcinomas on the p53-responsive element (p53RE) of the MDM2 gene

Gorgoulis

Zacharatos²,

Manolis³

et al. 1998

Br J Cancer

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Summary The present study represents a continuation of previous works in which we observed that lung carcinomas co-expressing MDM2 protein and p53 mutants (mt p53) exhibited more aggressive behaviour. In the above studies, we suggested a 'gain of function' mechanism of mt p53 proteins based on the fact that the MDM2 gene possesses a p53-responsive element (MDM2-p53RE). In this study, to prove our hypothesis, we selected 12 cases from a series of 51 bronchogenic carcinomas. In these 12 cases, we examined the ability of the expressed mt p53 to bind the MDM2-p53RE and correlated the findings with MDM2 expression. Furthermore, we constructed four of these p53 mutants and studied their transactivation properties by co-transfecting them with a reporter plasmid carrying MDM2-p53RE in the p53 null non-smallcell lung carcinoma cell line (NSCLC) H1299. We observed mutant p53 protein DNA-binding activity, which depended on the nature and the position of the amino acid substitution. The fact that the cases with DNA-binding activity were accompanied with MDM2 protein isoforms' overexpression is indicative of a 'gain of function' phenotype. This hypothesis was enforced by the findings of the transfection experiments, which revealed that certain p53 mutants enhanced the expression of the luciferase reporter gene either directly or indirectly via a dominant positive effect on the wild-type p53. In conclusion, this work is one first attempt to examine if the deregulation of the p53/MDM2 autoregulatory feedback loop is due to novel properties of certain p53 mutants in the specific environment of a subset of bronchogenic carcinomas.Keywords: p53 mutations; p53-responsive element; MDM2 gene; MDM2 isoforms; lung cancer The p53 oncosuppressor gene is mapped to chromosomal region 17pl3 and encodes a 393 amino acid (aa), 53-kDa nuclear phosphoprotein. The protein is divided into three main structural and functional domains. The first 42 amino acids at the N-terminus constitute the transactivation domain, the residues between amino acids 120 and 290 make up the sequence-specific DNA binding domain, whereas residues 310-393 at the C-terminus contain the nuclear localization signals, the tetramerization domain and the extreme carboxy-terminus that allosterically regulates p53 specific DNA binding. p53 protein is involved in vital aspects of the cell life, such as control of cell cycle checkpoints G, and G2, maintaining genomic integrity, DNA repair, replication, transcription, programmed cell death (apoptosis) and differentiation. Functional loss of p53, mostly via mutations, is considered the most common genetic lesion in human cancer (Greenblatt et al, 1994). Therefore, an understanding of the functions of p53 may help elucidate key steps in carcinogenesis. The cellular effects of p53 are mediated either by protein-protein interaction or by binding to DNA regulatory elements. In the first case, p53 interacts with factors of the replication, transcription and repair machinery (reviewed by:

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Transcriptional activation of the human proliferating-cell nuclear antigen promoter by p53.

Abstract: Proliferating-cell nuclear antigen (PCNA) is a DNA damage-inducible protein that

Cited by 115 publications

References 60 publications

Effects of growth hormone-releasing hormone and its agonistic and antagonistic analogs in cancer and non-cancerous cell lines

Effects of growth hormone-releasing hormone and its agonistic and antagonistic analogs in cancer and non-cancerous cell lines

DNA damage-associated cell cycle and cell death control is differentially modulated by caffeine in clones with p53 mutations

Effects of p53 mutants derived from lung carcinomas on the p53-responsive element (p53RE) of the MDM2 gene

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