Roles of p53 Family Structure and Function in Non-Canonical Response Element Binding and Activation

Cai, Bi-He; Chao, Chung-Faye; Huang, Hsiang-Chi; Lee, Hsueh-Yi; Kannagi, Reiji; Chen, Jang-Yi

doi:10.3390/ijms20153681

Cited by 19 publications

(24 citation statements)

References 130 publications

(150 reference statements)

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“…However, our study indicated that p53 may affect the reporter activity of the reporter vector containing the DNA fragment (−567 to −363), which does not have a putative p53 binding site. The majority of gene expressions modulated by p53 generally occurred through consensus sequences other than that of the p53 DNA-binding site [42,43]. Our results confirmed that maspin is a target gene of PTEN and p53, and should be referred to as an anti-tumor gene in bladder carcinoma cells.…”

Section: Discussionsupporting

confidence: 77%

Maspin is a PTEN-Upregulated and p53-Upregulated Tumor Suppressor Gene and Acts as an HDAC1 Inhibitor in Human Bladder Cancer

Lin

Tsui

Chang

et al. 2019

Cancers

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Maspin is a member of the clade B serine protease inhibitor superfamily and exhibits diverse regulatory effects in various types of solid tumors. We compared the expressions of maspin and determined its potential biological functions and regulatory mechanisms in bladder carcinoma cells in vitro and in vivo. The results of RT-qPCR indicated that maspin expressed significantly lower levels in the bladder cancer tissues than in the paired normal tissues. The immunohistochemical assays of human bladder tissue arrays revealed similar results. Maspin-knockdown enhanced cell invasion whereas the overexpression of maspin resulted in the opposite process taking place. Knockdown of maspin also enhanced tumorigenesis in vivo and downregulated protein levels of acetyl-histone H3. Moreover, in bladder carcinoma cells, maspin modulated HDAC1 target genes, including cyclin D1, p21, MMP9, and vimentin. Treatment with MK2206, which is an Akt inhibitor, upregulated maspin expression, whereas PTEN-knockdown or PTEN activity inhibitor (VO-OHpic) treatments demonstrated reverse results. The ectopic overexpression of p53 or camptothecin treatment induced maspin expression. Our study indicated that maspin is a PTEN-upregulated and p53-upregulated gene that blocks cell growth in vitro and in vivo, and may act as an HDAC1 inhibitor in bladder carcinoma cells. We consider that maspin is a potential tumor suppressor gene in bladder cancer.

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Section: Discussionsupporting

confidence: 77%

Maspin is a PTEN-Upregulated and p53-Upregulated Tumor Suppressor Gene and Acts as an HDAC1 Inhibitor in Human Bladder Cancer

Lin

Tsui

Chang

et al. 2019

Cancers

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“…ing between the two half-sites, ranging from 0-13 bp 8,9 . Hence the helical phasing between the two half sites could differ, which has the potential to impact the binding of p53 to DNA or the kinetic stability of complexes.…”

Section: Increasing the Spacing Between Half Sites Impacts The Populamentioning

confidence: 99%

Single molecule studies reveal that p53 tetramers dynamically bind response elements containing one or two half sites

Kugel

Goodrich

2020

Sci Rep

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The tumor suppressor protein p53 is critical for cell fate decisions, including apoptosis, senescence, and cell cycle arrest. p53 is a tetrameric transcription factor that binds DNA response elements to regulate transcription of target genes. p53 response elements consist of two decameric half-sites, and data suggest one p53 dimer in the tetramer binds to each half-site. Despite a broad literature describing p53 binding DNA, unanswered questions remain, due partly to the need for more quantitative and structural studies with full length protein. Here we describe a single molecule fluorescence system to visualize full length p53 tetramers binding DNA in real time. The data revealed a dynamic interaction in which tetrameric p53/DNA complexes assembled and disassembled without a dimer/DNA intermediate. On a wild type DNA containing two half sites, p53/DNA complexes existed in two kinetically distinct populations. p53 tetramers bound response elements containing only one half site to form a single population of complexes with reduced kinetic stability. Altering the spacing and helical phasing between two half sites affected both the population distribution of p53/DNA complexes and their kinetic stability. Our real time single molecule measurements of full length p53 tetramers binding DNA reveal the parameters that define the stability of p53/DNA complexes, and provide insight into the pathways by which those complexes assemble.

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“…Disrupting the helical phasing between half sites destabilizes tetrameric p53/DNA complexes p53 REs can have variable spacing between the two half-sites, ranging from 0-13 bp (8,9). Hence, the helical phasing between the two half sites can differ, potentially impacting the binding of p53 to DNA or the kinetic stability of complexes.…”

Section: P53 Tetramers Bind To Dnas Containing Either One or Two Halfmentioning

confidence: 99%

“…To activate transcription, p53 must recognize and bind to p53 REs in DNA. The p53 RE is composed of two 10 bp half site sequences with 0 to 13 base pairs of spacing in between (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Single molecule studies reveal that p53 tetramers dynamically bind response elements containing one or two half sites

Kugel

Goodrich

2019

Preprint

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The tumor suppressor protein p53 is at the nexus of cell fate decisions, including apoptosis, senescence, and cell cycle arrest. p53 is a tetrameric transcription factor that binds to DNA response elements to regulate transcription of its target genes, a process activated by cellular stress. p53 response elements consist of two decameric half-sites, and most data suggest one p53 dimer in the tetramer binds to each half-site. Despite a broad literature describing p53 binding to DNA, unanswered questions remain, due in part to the need for more quantitative and structural studies with the full length protein. Here we describe a single molecule fluorescence system to visualize full length p53 tetramers binding to DNA in real time. The data reveal a dynamic interaction with many p53 binding and dissociation events occurring on single DNA molecules over minutes. We found that p53 tetramers bound to response elements containing only a single half site. The kinetic stability of tetramer/DNA complexes depended on the number of half sites and the helical phasing between them, with the most stable complexes forming on DNA containing two adjacent half sites. The forward rate of binding was not strongly impacted when one half site was mutated. These studies provide real time kinetic measurements of full length p53 tetramers binding to single molecules of DNA, and reveal new insight into the mechanisms by which this nucleoprotein complex forms.

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Roles of p53 Family Structure and Function in Non-Canonical Response Element Binding and Activation

Cited by 19 publications

References 130 publications

Maspin is a PTEN-Upregulated and p53-Upregulated Tumor Suppressor Gene and Acts as an HDAC1 Inhibitor in Human Bladder Cancer

Maspin is a PTEN-Upregulated and p53-Upregulated Tumor Suppressor Gene and Acts as an HDAC1 Inhibitor in Human Bladder Cancer

Single molecule studies reveal that p53 tetramers dynamically bind response elements containing one or two half sites

Single molecule studies reveal that p53 tetramers dynamically bind response elements containing one or two half sites

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