Double-Stranded-RNA-Activated Protein Kinase PKR Enhances Transcriptional Activation by Tumor Suppressor p53

ABSTRACT The tumor suppressor p53 plays a key role in inducing G1 arrest and apoptosis following DNA damage. The double-stranded-RNA-activated protein PKR is a serine/threonine interferon (IFN)-inducible kinase which plays an important role in regulation of gene expression at both transcriptional and translational levels. Since a cross talk between IFN-inducible proteins and p53 had already been established, we investigated whether and how p53 function was modulated by PKR. We analyzed p53 function in several cell lines derived from PKR+/+ and PKR−/− mouse embryonic fibroblasts (MEFs) after transfection with the temperature-sensitive (ts) mutant of mouse p53 [p53(Val135)]. Here we report that transactivation of transcription by p53 and G0/G1 arrest were impaired in PKR−/− cells upon conditions that ts p53 acquired a wild-type conformation. Phosphorylation of mouse p53 on Ser18 was defective in PKR−/− cells, consistent with an impaired transcriptional induction of the p53-inducible genes encoding p21WAF/Cip1 and Mdm2. In addition, Ser18 phosphorylation and transcriptional activation by mouse p53 were diminished in PKR−/− cells after DNA damage induced by the anticancer drug adriamycin or γ radiation but not by UV radiation. Furthermore, the specific phosphatidylinositol-3 (PI-3) kinase inhibitor LY294002 inhibited the induction of phosphorylation of Ser18 of p53 by adriamycin to a higher degree in PKR+/+ cells than in PKR−/− cells. These novel findings suggest that PKR enhances p53 transcriptional function and implicate PKR in cell signaling elicited by a specific type of DNA damage that leads to p53 phosphorylation, possibly through a PI-3 kinase pathway.

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Tumor Suppressor p53 Stimulates the Expression of Epstein-Barr Virus Latent Membrane Protein 1

Journal of Virology ◽

10.1128/jvi.00312-17 ◽

2017 ◽

Vol 91 (20) ◽

Cited By ~ 6

Author(s):

Qianli Wang ◽

Amy Lingel ◽

Vicki Geiser ◽

Zachary Kwapnoski ◽

Luwen Zhang

Keyword(s):

Dna Damage ◽

Tumor Suppressor ◽

Epstein Barr Virus ◽

Latent Membrane Protein ◽

Latent Membrane Protein 1 ◽

Tumor Suppressor P53 ◽

Viral Oncogene ◽

Barr Virus ◽

Lmp1 Expression ◽

Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is associated with multiple human malignancies. EBV latent membrane protein 1 (LMP1) is required for the efficient transformation of primary B lymphocytes in vitro and possibly in vivo. The tumor suppressor p53 plays a seminal role in cancer development. In some EBV-associated cancers, p53 tends to be wild type and overly expressed; however, the effects of p53 on LMP1 expression is not clear. We find LMP1 expression to be associated with p53 expression in EBV-transformed cells under physiological and DNA damaging conditions. DNA damage stimulates LMP1 expression, and p53 is required for the stimulation. Ectopic p53 stimulates endogenous LMP1 expression. Moreover, endogenous LMP1 blocks DNA damage-mediated apoptosis. Regarding the mechanism of p53-mediated LMP1 expression, we find that interferon regulatory factor 5 (IRF5), a direct target of p53, is associated with both p53 and LMP1. IRF5 binds to and activates a LMP1 promoter reporter construct. Ectopic IRF5 increases the expression of LMP1, while knockdown of IRF5 leads to reduction of LMP1. Furthermore, LMP1 blocks IRF5-mediated apoptosis in EBV-infected cells. All of the data suggest that cellular p53 stimulates viral LMP1 expression, and IRF5 may be one of the factors for p53-mediated LMP1 stimulation. LMP1 may subsequently block DNA damage- and IRF5-mediated apoptosis for the benefits of EBV. The mutual regulation between p53 and LMP1 may play an important role in EBV infection and latency and its related cancers. IMPORTANCE The tumor suppressor p53 is a critical cellular protein in response to various stresses and dictates cells for various responses, including apoptosis. This work suggests that an Epstein-Bar virus (EBV) principal viral oncogene is activated by cellular p53. The viral oncogene blocks p53-mediated adverse effects during viral infection and transformation. Therefore, the induction of the viral oncogene by p53 provides a means for the virus to cope with infection and DNA damage-mediated cellular stresses. This seems to be the first report that p53 activates a viral oncogene; therefore, the discovery would be interesting to a broad readership from the fields of oncology to virology.

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Transcriptional Activation of the p53 Tumor Suppressor Gene Provides a Rapid Protective Mechanism against DNA Damage during S-phase of the Cell Cycle

Journal of Leukemia ◽

10.4172/2329-6917.1000e102 ◽

2013 ◽

Vol 01 (03) ◽

Author(s):

David Reisman

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Transcriptional Activation ◽

Suppressor Gene ◽

S Phase ◽

Protective Mechanism ◽

P53 Tumor Suppressor ◽

P53 Tumor Suppressor Gene

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DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death

Molecules ◽

10.3390/molecules24173175 ◽

2019 ◽

Vol 24 (17) ◽

pp. 3175

Author(s):

Katsuhiko Itoh ◽

Takahiro Ebata ◽

Hiroaki Hirata ◽

Takeru Torii ◽

Wataru Sugimoto ◽

...

Keyword(s):

Dna Damage ◽

Cell Death ◽

Tumor Suppressor ◽

Dependent Manner ◽

Tumor Suppressor P53 ◽

P53 Family ◽

Gene Encoding ◽

Myotonic Dystrophy Protein Kinase ◽

Induced Apoptosis ◽

Actomyosin Contraction

Tumor suppressor p53 plays an integral role in DNA-damage induced apoptosis, a biological process that protects against tumor progression. Cell shape dramatically changes when cells undergo apoptosis, which is associated with actomyosin contraction; however, it remains entirely elusive how p53 regulates actomyosin contraction in response to DNA-damaging agents. To identify a novel p53 regulating gene encoding the modulator of myosin, we conducted DNA microarray analysis. We found that, in response to DNA-damaging agent doxorubicin, expression of myotonic dystrophy protein kinase (DMPK), which is known to upregulate actomyosin contraction, was increased in a p53-dependent manner. The promoter region of DMPK gene contained potential p53-binding sequences and its promoter activity was increased by overexpression of the p53 family protein p73, but, unexpectedly, not of p53. Furthermore, we found that doxorubicin treatment induced p73 expression, which was significantly attenuated by downregulation of p53. These data suggest that p53 induces expression of DMPK through upregulating p73 expression. Overexpression of DMPK promotes contraction of the actomyosin cortex, which leads to formation of membrane blebs, loss of cell adhesion, and concomitant caspase activation. Taken together, our results suggest the existence of p53-p73-DMPK axis which mediates DNA-damage induced actomyosin contraction at the cortex and concomitant cell death.

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Attenuation of DNA damage checkpoint by PBK, a novel mitotic kinase, involves protein–protein interaction with tumor suppressor p53

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2007.04.125 ◽

2007 ◽

Vol 358 (1) ◽

pp. 181-188 ◽

Cited By ~ 30

Author(s):

Asit K. Nandi ◽

Tamara Ford ◽

Daniel Fleksher ◽

Brian Neuman ◽

Aaron P. Rapoport

Keyword(s):

Dna Damage ◽

Tumor Suppressor ◽

Protein Interaction ◽

Dna Damage Checkpoint ◽

Tumor Suppressor P53 ◽

Protein Protein Interaction ◽

Mitotic Kinase

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Sp1 Plays a Critical Role in the Transcriptional Activation of the Human Cyclin-dependent Kinase Inhibitor p21WAF1/Cip1Gene by the p53 Tumor Suppressor Protein

Journal of Biological Chemistry ◽

10.1074/jbc.m104130200 ◽

2001 ◽

Vol 276 (31) ◽

pp. 29116-29125 ◽

Cited By ~ 119

Author(s):

George Koutsodontis ◽

Ioannis Tentes ◽

Paraskevi Papakosta ◽

Aristidis Moustakas ◽

Dimitris Kardassis

Keyword(s):

Tumor Suppressor ◽

Transcriptional Activation ◽

Kinase Inhibitor ◽

Critical Role ◽

Tumor Suppressor Protein ◽

Cyclin Dependent Kinase ◽

P53 Tumor Suppressor ◽

Cyclin Dependent Kinase Inhibitor ◽

P53 Tumor Suppressor Protein

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Cellular DNA Damage Response to Zinc Oxide Nanoparticles Hinges on the Tumor Suppressor p53 Pathway

Proceedings of the 14th Asia Pacific Confederation of Chemical Engineering Congress ◽

10.3850/978-981-07-1445-1_805 ◽

2012 ◽

Author(s):

David Leong

Keyword(s):

Dna Damage ◽

Zinc Oxide ◽

Tumor Suppressor ◽

Dna Damage Response ◽

Zinc Oxide Nanoparticles ◽

Oxide Nanoparticles ◽

Tumor Suppressor P53 ◽

P53 Pathway ◽

Damage Response ◽

Cellular Dna

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Inhibitory role of E2F-1 in the regulation of tumor suppressor p53 during DNA damage response

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2012.03.108 ◽

2012 ◽

Vol 421 (1) ◽

pp. 57-63 ◽

Cited By ~ 9

Author(s):

Yukari Yoshihara ◽

Dan Wu ◽

Natsumi Kubo ◽

Meixiang Sang ◽

Akira Nakagawara ◽

...

Keyword(s):

Dna Damage ◽

Tumor Suppressor ◽

Dna Damage Response ◽

Tumor Suppressor P53 ◽

Inhibitory Role ◽

Damage Response

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Condensin locates at transcriptional termination sites in mitosis, possibly releasing mitotic transcripts

Open Biology ◽

10.1098/rsob.190125 ◽

2019 ◽

Vol 9 (10) ◽

pp. 190125 ◽

Cited By ~ 3

Author(s):

Norihiko Nakazawa ◽

Orie Arakawa ◽

Mitsuhiro Yanagida

Keyword(s):

Transcriptional Activation ◽

Temperature Sensitive ◽

Growth Defects ◽

Transcriptional Termination ◽

Genome Wide ◽

Transcription Sites ◽

Cold Sensitive ◽

Inducible Genes ◽

Mitotic Chromosome Condensation

Condensin is an essential component of chromosome dynamics, including mitotic chromosome condensation and segregation, DNA repair, and development. Genome-wide localization of condensin is known to correlate with transcriptional activity. The functional relationship between condensin accumulation and transcription sites remains unclear, however. By constructing the auxin-inducible degron strain of condensin, herein we demonstrate that condensin does not affect transcription itself. Instead, RNA processing at transcriptional termination appears to define condensin accumulation sites during mitosis, in the fission yeast Schizosaccharomyces pombe . Combining the auxin-degron strain with the nda3 β-tubulin cold-sensitive (cs) mutant enabled us to inactivate condensin in mitotically arrested cells, without releasing the cells into anaphase. Transcriptional activation and termination were not affected by condensin's degron-mediated depletion, at heat-shock inducible genes or mitotically activated genes. On the other hand, condensin accumulation sites shifted approximately 500 bp downstream in the auxin-degron of 5′-3′ exoribonuclease Dhp1, in which transcripts became aberrantly elongated, suggesting that condensin accumulates at transcriptionally terminated DNA regions. Growth defects in mutant strains of 3′-processing ribonuclease and polyA cleavage factors were additive in condensin temperature-sensitive (ts) mutants. Considering condensin's in vitro activity to form double-stranded DNAs from unwound, single-stranded DNAs or DNA-RNA hybrids, condensin-mediated processing of mitotic transcripts at the 3′-end may be a prerequisite for faithful chromosome segregation.

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