p53 controls hPar1 function and expression

Salah, Zaidoun; Haupt, Sue; Maoz, Myriam; Baraz, Lea; Rotter, Varda; Peretz, Tamar; Haupt, Ygal; Bar-Shavit, Rachel

doi:10.1038/onc.2008.324

Cited by 19 publications

(17 citation statements)

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“…These data demonstrate the specific inhibitory effect of p53WT on TFF2 promoter activity. Moreover, p53R175H upregulated the expression of c-Fos in Kato-III cells, consistent with previous report that p53R175H increased the expression of c-Fos in p53-null H1299 cells (39) (Fig. 3F).…”

Section: Resultssupporting

confidence: 92%

p53 inhibition of AP1-dependent TFF2 expression induces apoptosis and inhibits cell migration in gastric cancer cells

Alfred²,

Ai³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Overexpression of trefoil factor 2 (TFF2) is associated with increased cell migration, resistance to apoptosis, and possibly increased gastric cancer invasion. Dysregulation of p53 is frequently observed in preneoplastic conditions of the stomach. Here, we investigated the effect of p53 on the expression and function of TFF2 in gastric cancer cell lines. Gene expression was determined by reverse transcription-polymerase chain reaction, and promoter activity was assessed by dual luciferase reporter assays. Apoptosis was detected by flow cytometry, and cell migration was evaluated by the Boyden chamber assay. Exogenous expression of p53 dose dependently inhibited endogenous TFF2 mRNA, protein, and promoter activity and resulted in induction of cell apoptosis and inhibition of cell migration. Downregulation of TFF2 by small interfering RNA sensitized gastric cancer cells to drug-induced p53-dependent apoptosis. Addition of human TFF2 peptide reversed p53-dependent apoptosis and inhibition of cell migration. The p53-responsive element was mapped to an AP-1-like cis-element at -182 bp upstream of the TFF2 transcription start site. Mutation of this AP-1-like element abrogated p53-mediated inhibition of TFF2 promoter activity. Gel shift and chromatin immunoprecipitation assays demonstrated that c-Jun and c-Fos bind to this AP-1-like element. Ectopic expression of c-Jun/c-Fos or p300 or treatment of cells with phorbol 12-myristate 13-acetate (PMA) stimulated endogenous TFF2 mRNA expression and promoter activity, and p53 inhibited the effects of AP-1 and PMA on TFF2. p53 induces cell apoptosis and inhibits cell migration in part by downregulating TFF2 expression through an AP-1-like site, suggesting that TFF2 may be an important downstream target of p53.

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Section: Resultssupporting

confidence: 92%

p53 inhibition of AP1-dependent TFF2 expression induces apoptosis and inhibits cell migration in gastric cancer cells

Alfred²,

Ai³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…However, studies from the cancer literature show that the PAR1 promoter is regulated by p53, the androgen receptor, and activator protein 2 (AP2). [88][89][90] Although PAR expression has not been directly connected to epigenetic factors, recent studies have correlated hypomethylation of f2rl3 (the PAR4 gene) to smoking in multiple populations. [91][92][93][94] The decreased methylation of f2rl3 is linked to an increase in mortality due to coronary heart disease when other factors are controlled and is a potential biomarker.…”

Section: Regulation Of Par Expression and Polymorphismsmentioning

confidence: 99%

Protease-activated receptors in hemostasis

Nieman

2016

Blood

126

123

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Protease signaling in cells elicits multiple physiologically important responses via protease-activated receptors (PARs). There are 4 members of this family of G-protein–coupled receptors (PAR1-4). PARs are activated by proteolysis of the N terminus to reveal a tethered ligand. The rate-limiting step of PAR signaling is determined by the efficiency of proteolysis of the N terminus, which is regulated by allosteric binding sites, cofactors, membrane localization, and receptor dimerization. This ultimately controls the initiation of PAR signaling. In addition, these factors also control the cellular response by directing signaling toward G-protein or β-arrestin pathways. PAR1 signaling on endothelial cells is controlled by the activating protease and heterodimerization with PAR2 or PAR3. As a consequence, the genetic and epigenetic control of PARs and their cofactors in physiologic and pathophysiologic conditions have the potential to influence cellular behavior. Recent studies have uncovered polymorphisms that result in PAR4 sequence variants with altered reactivity that interact to influence platelet response. This further demonstrates how interactions within the plasma membrane can control the physiological output. Understanding the structural rearrangement following PAR activation and how PARs are allosterically controlled within the plasma membrane will determine how best to target this family of receptors therapeutically. The purpose of this article is to review how signaling from PARs is influenced by alternative cleavage sites and the physical interactions within the membrane. Going forward, it will be important to relate the altered signaling to the molecular arrangement of PARs in the cell membrane and to determine how these may be influenced genetically.

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“…Previous studies showed that these transactivation domain residues may interact with a number of proteins including Mdm2, adenovirus E1B 29, TAFs 30 and p300 31. In addition, p53-V173L, p53-R175H and p53-H179Q are commonly found in human cancers 32. Moreover, several p53 hotspot mutations (R175H, R248W and R273H) were found not only lost p53-dependent tumor suppressor activities, but also acquired new oncogenic activities to promote progression of cancers 33.…”

Section: Discussionmentioning

confidence: 99%

HOXA5 and p53 cooperate to suppress lung cancer cell invasion and serve as good prognostic factors in non-small cell lung cancer

Chang¹,

Chen²,

Hsieh³

et al. 2017

J. Cancer

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Lung cancer is the leading cause of cancer mortality worldwide and tumor metastasis is the major cause of cancer-related death. Our previous study suggested that Homeobox A5 (HOXA5) could inhibit lung cancer cell invasion via regulating cytoskeletal remodeling and involved in tumor metastasis. Recently, consensus HOX binding sites was found in the p53 gene promoter region. However, whether the HOXA5 could cooperate with p53 and contribute the inhibition of lung cancer cell invasion is still unclear. The aim of the current study is to elucidate the correlation of HOXA5 and p53 in tumor invasion and its prognostic influence in lung cancer patient specimens. Totally 71 cases of primary non-small cell lung cancer (NSCLC) were collected. The median follow-up period is 6.8 years. Immunohistochemical stain for p53 and HOXA5 were performed. Kaplan-Meier plot was done for overall survival analysis. In addition, lung cancer cell lines transfected with wild-type or mutated p53 constructs were overexpressed with HOXA5 for invasion assay. In human specimens, HOXA5 expressed mainly in the cytoplasm (54.1%) rather than nuclei (14.6%) of the NSCLC tumor part. The HOXA5 expression is higher in adenocarcinoma than in squamous cell carcinoma (P < 0.001). In addition, poor prognosis is seen in group with both non-immunoreactive for p53 and HOXA5. HOXA5 and p53 could cooperate to inhibit tumor cell invasion significantly partly by decreasing MMP2 activity in a concentration-dependent manner. Our studies provide new insights into how HOXA5 and p53 cooperate to contribute to the suppression of lung cancer cell invasion and play good prognostic roles in NSCLC.

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p53 controls hPar1 function and expression

Cited by 19 publications

References 50 publications

p53 inhibition of AP1-dependent TFF2 expression induces apoptosis and inhibits cell migration in gastric cancer cells

p53 inhibition of AP1-dependent TFF2 expression induces apoptosis and inhibits cell migration in gastric cancer cells

Protease-activated receptors in hemostasis

HOXA5 and p53 cooperate to suppress lung cancer cell invasion and serve as good prognostic factors in non-small cell lung cancer

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