IU Indianapolis ScholarWorks :: Browsing by Subject "p53"

Browsing by Subject "p53"

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Bmi1 promotes erythroid development through regulating ribosome biogenesis
(Wiley, 2015-03) Gao, Rui; Chen, Sisi; Kobayashi, Michihiro; Yu, Hao; Zhang, Yingchi; Wan, Yang; Young, Sara K.; Soltis, Anthony; Yu, Ming; Vemula, Sasidhar; Fraenkel, Ernest; Cantor, Alan; Antipin, Yevgeniy; Xu, Yang; Yoder, Mervin C.; Wek, Ronald C.; Ellis, Steven R.; Kapur, Reuben; Zhu, Xiaofan; Liu, Yan; Department of Pediatrics, Indiana University School of Medicine
While Polycomb group protein Bmi1 is important for stem cell maintenance, its role in lineage commitment is largely unknown. We have identified Bmi1 as a novel regulator of erythroid development. Bmi1 is highly expressed in mouse erythroid progenitor cells and its deficiency impairs erythroid differentiation. BMI1 is also important for human erythroid development. Furthermore, we discovered that loss of Bmi1 in erythroid progenitor cells results in decreased transcription of multiple ribosomal protein genes and impaired ribosome biogenesis. Bmi1 deficiency stabilizes p53 protein, leading to upregulation of p21 expression and subsequent G0/G1 cell cycle arrest. Genetic inhibition of p53 activity rescues the erythroid defects seen in the Bmi1 null mice, demonstrating that a p53-dependent mechanism underlies the pathophysiology of the anemia. Mechanistically, Bmi1 is associated with multiple ribosomal protein genes and may positively regulate their expression in erythroid progenitor cells. Thus, Bmi1 promotes erythroid development, at least in part through regulating ribosome biogenesis. Ribosomopathies are human disorders of ribosome dysfunction, including Diamond-Blackfan anemia (DBA) and 5q- syndrome, in which genetic abnormalities cause impaired ribosome biogenesis, resulting in specific clinical phenotypes. We observed that BMI1 expression in human hematopoietic stem and progenitor cells from patients with DBA is correlated with the expression of some ribosomal protein genes, suggesting that BMI1 deficiency may play a pathological role in DBA and other ribosomopathies.
Characterization of the MDM2 binding regions of ribosomal protein L5
(2010-07-20T16:29:38Z) Plummer, Kevin D.; Lu, Hua; Goebl, Mark, 1958-; Hurley, Thomas D., 1961-
The MDM2-p53 feedback loop is a well-characterized pathway. p53 is a transcription factor and regulates the transcriptional expression of genes that encode proteins responsible for cellular senescence, cell cycle arrest, apoptosis, and DNA repair. Various cellular stresses can result in p53 activation, including hypoxia, DNA damage by agents such as UV or IR, oncogenic signaling, nucleotide depletion and nucleolar stress from perturbation of ribosomal biogenesis. Under normal conditions, MDM2’s role in the pathway is to inhibit p53 function by directly binding to this protein and facilitating its ubiquitylation and 26S proteasome-mediated degradation. Under stressful cellular conditions, certain proteins interact with and rescue MDM2’s inhibition of p53. For example, upon exposure to small amounts of Actinomycin D, rRNA transcript synthesis is stalled resulting in the release of various ribosomal proteins including RPL5, RPL11 and RPL23; each of which has been shown to bind MDM2 within its central acidic domain and inhibit its ability to destabilize p53. Although the RPL5 binding region of MDM2 have been mapped in prior investigations, the MDM2-binding region(s) of RPL5 have yet to be characterized. By employing RPL5 deletion mutagenesis and in vitro GST-fusion protein-protein association assays with purified proteins, this dissertation attempts to elucidate those regions of RPL5 that may interact with MDM2. Normalizing RPL5-WT to 1.00, our study reveals that the basic N and C-terminals of RPL5 appear to bind with MDM2 while RPL5’s central region displays negligible binding to the central acidic domain of MDM2. Also, the possible meanings of these RPL5 MDM2 binding domains are discussed along with their utilization in potential future applications.
Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist
(American Association of Neurological Surgeons, 2017-02) Wang, Haiyan; Cai, Shanbao; Bailey, Barbara J.; Saadatzadeh, M. Reza; Ding, Jixin; Tonsing-Carter, Eva; Georgiadis, Taxiarchis M.; Gunter, T. Zachary; Long, Eric C.; Minto, Robert E.; Gordon, Kevin R.; Sen, Stephanie E.; Cai, Wenjing; Eitel, Jacob A.; Waning, David L.; Bringman, Lauren R.; Wells, Clark D.; Murray, Mary E.; Sarkaria, Jann N.; Gelbert, Lawrence M.; Jones, David R.; Cohen-Gadol, Aaron A.; Mayo, Lindsey D.; Shannon, Harlan E.; Pollok, Karen E.; Pediatrics, School of Medicine
OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein-protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein-protein interactions.
The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53
(American Society for Biochemistry and Molecular Biology, 2018-03-23) Madan, Esha; Parker, Taylor M.; Bauer, Matthias R.; Dhiman, Alisha; Pelham, Christopher J.; Nagane, Masaki; Kuppusamy, M. Lakshmi; Holmes, Matti; Holmes, Thomas R.; Shaik, Kranti; Shee, Kevin; Kiparoidze, Salome; Smith, Sean D.; Park, Yu-Soon A.; Gomm, Jennifer J.; Jones, Louise J.; Tomás, Ana R.; Cunha, Ana C.; Selvendiran, Karuppaiyah; Hansen, Laura A.; Fersht, Alan R.; Hideg, Kálmán; Gogna, Rajan; Kuppusamy, Periannan; Surgery, School of Medicine
p53 is an important tumor-suppressor protein that is mutated in more than 50% of cancers. Strategies for restoring normal p53 function are complicated by the oncogenic properties of mutant p53 and have not met with clinical success. To counteract mutant p53 activity, a variety of drugs with the potential to reconvert mutant p53 to an active wildtype form have been developed. However, these drugs are associated with various negative effects such as cellular toxicity, nonspecific binding to other proteins, and inability to induce a wildtype p53 response in cancer tissue. Here, we report on the effects of a curcumin analog, HO-3867, on p53 activity in cancer cells from different origins. We found that HO-3867 covalently binds to mutant p53, initiates a wildtype p53-like anticancer genetic response, is exclusively cytotoxic toward cancer cells, and exhibits high anticancer efficacy in tumor models. In conclusion, HO-3867 is a p53 mutant-reactivating drug with high clinical anticancer potential.
Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity
(Elsevier, 2019-03-12) Aho, Erin R.; Wang, Jing; Gogliotti, Rocco D.; Howard, Gregory C.; Phan, Jason; Acharya, Pankaj; Macdonald, Jonathan D.; Cheng, Ken; Lorey, Shelly L.; Lu, Bin; Wenzel, Sabine; Foshage, Audra M.; Alvarado, Joseph; Wang, Feng; Shaw, J. Grace; Zhao, Bin; Weissmiller, April M.; Thomas, Lance R.; Vakoc, Christopher R.; Hall, Matthew D.; Hiebert, Scott W.; Liu, Qi; Stauffer, Shaun R.; Fesik, Stephen W.; Tansey, William P.; Biochemistry and Molecular Biology, School of Medicine
The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.
Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness
(MDPI, 2016-12) Olivos, David J., III; Mayo, Lindsey D.; Pediatrics, School of Medicine
Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53’s functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53’s effects on stemness could lead to novel therapeutic strategies in cancer research. View Full-Text
Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness
(MDPI, 2016-11-26) Olivos III, David J.; Mayo, Lindsey D.; Department of Microbiology & Immunology, IU School of Medicine
Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53's functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53's effects on stemness could lead to novel therapeutic strategies in cancer research.
GCN2 eIF2 Kinase Promotes Prostate Cancer by Maintaining Amino Acid Homeostasis
(2024-04) Cordova E., Ricardo A.; Wek, Ronald C.; Staschke, Kirk A.; Pili, Roberto; Mosley, Amber L.; Elmendorf, Jeffrey S.; Zhang, Ji
Activation of the integrated stress response (ISR) contributes to the progression of many cancers, including prostate cancer (PCa). The ISR features a family of protein kinases that phosphorylate the eukaryotic translation initiation factor 2 (eIF2) during different stress conditions, repressing global protein synthesis. In parallel, eIF2 phosphorylation also enhances the translation of select gene transcripts, such as ATF4, which directs the transcription of ISR-target genes critical for stress adaptation. We reported that the eIF2 kinase GCN2 is a critical driver of the ISR in PCa and is crucial to maintaining amino acid (AA) homeostasis. GCN2 is activated in PCa due to AA limitation, resulting in increased expression of key AA transporters which providing nutrient import to fuel protein synthesis and metabolism that drive prostate tumor cell proliferation. Inhibition of GCN2 results in lowered expression of AA transporters, leading to severe depletion of intracellular AA and reduced proliferation in PCa. We identified purine biosynthesis as a key metabolic pathway dependent on GCN2. Inhibition of GCN2 and the accompanying depletion of AAs decreases purine levels in PCa cells, ultimately resulting in reduced ribosome biogenesis leading to the activation of a p53-dependent cell cycle checkpoint, termed the Impaired Ribosome Biogenesis Checkpoint (IRBC). Interestingly, induction of p53 promotes survival of PCa following GCN2 inhibition by halting cell cycle progression and reprogramming metabolism to restore metabolic homeostasis. We found that reductions in select AAs that impact nucleotide pools activate GCN2 and p53 in parallel, and that cooperation of these stress pathways is critical for maintaining AA and purine pools. Of importance, deletion of p53 sensitizes PCa cells to GCN2 inhibition suggesting that loss of p53 creates a dependency for GCN2. Of importance, we demonstrate that a small molecule inhibitor of GCN2 showed robust in vivo efficacy in androgen-sensitive and castrationresistant mouse models of PCa, supporting its therapeutic potential for the treatment of PCa.
Ginseng metabolite protopanaxadiol interferes with lipid metabolism and induces endoplasmic reticulum stress and p53 activation to promote cancer cell death
(Wiley, 2019-03) Jin, Hong Ri; Du, Charles H.; Wang, Chong-Zhi; Yuan, Chun-Su; Du, Wei; Pathology and Laboratory Medicine, School of Medicine
Protopanaxadiol (PPD), a ginseng metabolite generated by the gut bacteria, was shown to induce colorectal cancer cell death and enhance the anticancer effect of chemotherapeutic agent 5-FU. However, the mechanism by which PPD promotes cancer cell death is not clear. In this manuscript, we showed that PPD activated p53 and ER stress and induced expression of BH3-only proteins Puma and Noxa to promote cell death. Induction of Puma by PPD was p53-dependent while induction of Noxa was p53-independent. On the other hand, PPD also induced pro-survival mechanisms including autophagy and expression of Bcl2 family apoptosis regulator Mcl-1. Inhibition of autophagy or knockdown of Mcl-1 significantly enhanced PPD-induced cell death. Interestingly, PPD inhibited expression of genes involved in fatty acid and cholesterol biosynthesis and induced synergistic cancer cell death with fatty acid synthase inhibitor cerulenin. As PPD-induced ER stress was not significantly affected by inhibition of new protein synthesis, we suggest PPD may induce ER stress directly through causing lipid disequilibrium.
Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53.
(Impact Journals, 2016-05-10) DasGupta, Twishasri; Nweze, Emeka I.; Yue, Hong; Wang, Liming; Jin, Jessica; Ghosh, Santosh K.; Kawsar, Hameem I.; Zender, Chad; Androphy, Elliot J.; Weinberg, Aaron; McCormick, Thomas S.; Jin, Ge; Department of Dermatology, IU School of Medicine
Human β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexpressed in oral dysplastic lesions and fosters a tumor-promoting microenvironment. Expression of hBD3 is induced by the epidermal growth factor receptor signaling pathway. Here we describe a novel pathway through which the high-risk human papillomavirus type-16 (HPV-16) oncoprotein E6 induces hBD3 expression in mucosal keratinocytes. Ablation of E6 by siRNA induces the tumor suppressor p53 and diminishes hBD3 in HPV-16 positive CaSki cervical cancer cells and UM-SCC-104 head and neck cancer cells. Malignant cells in HPV-16-associated oropharyngeal cancer overexpress hBD3. HPV-16 E6 induces hBD3 mRNA expression, peptide production and gene promoter activity in mucosal keratinocytes. Reduction of cellular levels of p53 stimulates hBD3 expression, while activation of p53 by doxorubicin inhibits its expression in primary oral keratinocytes and CaSki cells, suggesting that p53 represses hBD3 expression. A p53 binding site in the hBD3 gene promoter has been identified by using electrophoretic mobility shift assays and chromatin immunoprecipitation (ChIP). In addition, the p63 protein isoform ΔNp63α, but not TAp63, stimulated transactivation of the hBD3 gene and was co-expressed with hBD3 in head and neck cancer specimens. Therefore, high-risk HPV E6 oncoproteins may stimulate hBD3 expression in tumor cells to facilitate tumorigenesis of HPV-associated head and neck cancer.

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