scholarly journals Recent Advances in p53 Research and Cancer Treatment

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Kazufumi Suzuki ◽  
Hisahiro Matsubara
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Human Cancer ◽  
Basic Function ◽  
Clinical Applications ◽  
Mutant P53 ◽  
Cycle Arrest ◽  
Recent Advances ◽  
Response To Stress

TP53, encoding p53, is one of the most famous tumor suppressor genes. The majority of human cancers demonstrate the inactivation of the p53 pathway. Mutant p53 not only, no longer, functions as a tumor suppressor but can also exert tumor-promoting effects. The basic function of p53 is to respond to cellular stress. We herein review the recent advances in p53 research and focus on apoptosis, cell cycle arrest, and senescence in response to stress. We also review the clinical applications of p53-based therapy for human cancer.

A Stapled p53 Helix Targets HDMX to Overcome Nutlin-3 Resistance and Reactivate the p53 Tumor Suppressor Pathway in Cancer

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2645-2645
Author(s):  
Federico Bernal ◽  
Mark Wade ◽  
Amy M. Silverstein ◽  
Gregory L. Verdine ◽  
Geoffrey M. Wahl ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Ubiquitin Ligase ◽  
Human Cancer ◽  
Transactivation Domain ◽  
Binding Interaction ◽  
P53 Tumor Suppressor ◽  
Cycle Arrest

Abstract p53 is a transcription factor that induces cell cycle arrest or apoptosis in response to DNA damage and cellular stress, and thereby plays a critical role in protecting cells from malignant transformation. The E3 ubiquitin ligase HDM2 controls p53 levels through a direct binding interaction that neutralizes the transactivation activity of p53 and targets it for degradation via the ubiquitylation-proteasomal pathway. Whereas the HDM2-homologue HDMX lacks ubiquitin ligase function, it participates in regulating the p53 axis by heterodimerizing with HDM2 and sequestering p53 through protein interaction. Loss of p53 activity, either by deletion, mutation, or HDM2/HDMX overexpression, is the most common defect in human cancer. Tumors expressing wild type p53 are rendered vulnerable by pharmacologic approaches that stabilize and upregulate p53. In this context, HDM2 and HDMX have emerged as independent therapeutic targets for restoring p53 activity and resensitizing cancer cells to apoptosis in vitro and in vivo. The small molecule nutlin-3 is an effective antagonist of the p53-HDM2 interaction. However, several studies have demonstrated the inability of nutlin-3 to disrupt the p53-HDMX complex, rendering tumor cells that overexpress HDMX nutlin-3-resistant. We have previously described the synthesis and characterization of a hydrocarbon-stapled alpha-helical p53 peptide (SAH-p53-8) that binds HDM2 with low nanomolar affinity, targets HDM2 in situ, and reactivates the p53 tumor suppressor pathway in HDM2-overexpressing osteosarcoma cells. We now report that SAH-p53-8 binds HDMX with even higher affinity, co-immunoprecipitates with endogenous HDMX, and induces apoptosis and cell cycle arrest in nutlin-3-resistant cancer cells that overexpress HDMX. Thus, by inserting a chemical staple into a peptide fragment of the p53 transactivation domain, we have generated the first bifunctional inhibitor of HDM2 and HDMX, enabling the investigation and pharmacologic modulation of both targets in human cancer.

scholarly journals Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Amada R. López de la Oliva ◽  
José A. Campos-Sandoval ◽  
María C. Gómez-García ◽  
Carolina Cardona ◽  
Mercedes Martín-Rufián ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Human Cancer ◽  
Metabolic Reprogramming ◽  
Nuclear Targeting ◽  
Human Cancer Cells ◽  
Cycle Arrest

AbstractGlutaminase (GA) catalyzes the first step in mitochondrial glutaminolysis playing a key role in cancer metabolic reprogramming. Humans express two types of GA isoforms: GLS and GLS2. GLS isozymes have been consistently related to cell proliferation, but the role of GLS2 in cancer remains poorly understood. GLS2 is repressed in many tumor cells and a better understanding of its function in tumorigenesis may further the development of new therapeutic approaches. We analyzed GLS2 expression in HCC, GBM and neuroblastoma cells, as well as in monkey COS-7 cells. We studied GLS2 expression after induction of differentiation with phorbol ester (PMA) and transduction with the full-length cDNA of GLS2. In parallel, we investigated cell cycle progression and levels of p53, p21 and c-Myc proteins. Using the baculovirus system, human GLS2 protein was overexpressed, purified and analyzed for posttranslational modifications employing a proteomics LC-MS/MS platform. We have demonstrated a dual targeting of GLS2 in human cancer cells. Immunocytochemistry and subcellular fractionation gave consistent results demonstrating nuclear and mitochondrial locations, with the latter being predominant. Nuclear targeting was confirmed in cancer cells overexpressing c-Myc- and GFP-tagged GLS2 proteins. We assessed the subnuclear location finding a widespread distribution of GLS2 in the nucleoplasm without clear overlapping with specific nuclear substructures. GLS2 expression and nuclear accrual notably increased by treatment of SH-SY5Y cells with PMA and it correlated with cell cycle arrest at G2/M, upregulation of tumor suppressor p53 and p21 protein. A similar response was obtained by overexpression of GLS2 in T98G glioma cells, including downregulation of oncogene c-Myc. Furthermore, human GLS2 was identified as being hypusinated by MS analysis, a posttranslational modification which may be relevant for its nuclear targeting and/or function. Our studies provide evidence for a tumor suppressor role of GLS2 in certain types of cancer. The data imply that GLS2 can be regarded as a highly mobile and multilocalizing protein translocated to both mitochondria and nuclei. Upregulation of GLS2 in cancer cells induced an antiproliferative response with cell cycle arrest at the G2/M phase.

Opposing Effects of Dexamethasone on Lenalidomide Activity in Multiple Myeloma: Additive/Synergistic Effects on Anti-Proliferative Activity on Myeloma Cells and Antagonistic Effects on Immune Function

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2761-2761
Author(s):  
Peter H Schafer ◽  
Anita K Gandhi ◽  
Ling-Hua Zhang ◽  
Jian Kang ◽  
Lori Capone ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Tumor Suppressor Genes ◽  
Low Dose ◽  
Cell Function ◽  
Nk Cell ◽  
Cycle Arrest

Abstract Lenalidomide (Revlimid®) is approved for the treatment of previously treated multiple myeloma (MM) in combination with dexamethasone. Single agent lenalidomide has direct antiproliferative activity against MM cells and direct immunomodulatory activity via costimulation of T cell and natural killer (NK) cell responses. The ECOG Phase III trial in newly diagnosed MM (E4A03) reported that low dose (40 mg/d on days 1, 8, 15 & 22 of a 28-day cycle) dexamethasone in combination with lenalidomide showed an overall survival advantage when compared with the higher, standard-dose (40 mg/d on days 1-,4, 9–12 & 17–20 of a 28-day cycle) of dexamethasone that is used in combination with lenalidomide. We have examined the pharmacological activity of lenalidomide in combination with dexamethasone with respect to direct MM antiproliferative and T/NK cell stimulation in vitro. Antiproliferative activity against various MM cell lines was associated with increased expression of tumor suppressor genes, including Egr1, Egr3, p21, and p27. The specific tumor suppressor genes induced varied among the MM cell lines, even among those that were sensitive to lenalidomide. Lenalidomide and dexamethasone induced cell cycle arrest in G0/G1 phase, activation of caspases 3/7, and apoptosis in the sensitive cell lines. The combination of lenalidomide and dexamethasone was partially additive in most MM cell lines, while the most dramatic combination effect observed was induction of p21 gene expression and apoptosis in LP-1 MM cells. In contrast to its synergistic effect on MM cell proliferation, dexamethasone was strongly antagonistic to the T and NK cell costimulatory effects of lenalidomide. Specifically, in primary human T cells dexamethasone inhibited lenalidomide-enhanced IL-2 production. Furthermore, in primary human NK cells dexamethasone inhibited lenalidomide-enhanced IFN-γ production. These findings suggest that the lenalidomide plus low-dose dexamethasone regimen may be able to facilitate the MM cell killing via induction of tumor suppressor gene expression, cell cycle arrest, and apoptosis, while allowing lenalidomide to enhance T and NK cell function to a greater magnitude. The enhanced survival with the low-dose dexamethasone schedule in MM patients suggests exploring further dosing schedules of dexamethasone in combination with lenalidomide in this population, with measurement of biomarkers of T and NK cell function.

scholarly journals Tumor Suppressor Inactivation in the Pathogenesis of Adult T-Cell Leukemia

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Christophe Nicot
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Tumor Suppressors ◽  
Epigenetic Mechanisms ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Cycle Arrest

Tumor suppressor functions are essential to control cellular proliferation, to activate the apoptosis or senescence pathway to eliminate unwanted cells, to link DNA damage signals to cell cycle arrest checkpoints, to activate appropriate DNA repair pathways, and to prevent the loss of adhesion to inhibit initiation of metastases. Therefore, tumor suppressor genes are indispensable to maintaining genetic and genomic integrity. Consequently, inactivation of tumor suppressors by somatic mutations or epigenetic mechanisms is frequently associated with tumor initiation and development. In contrast, reactivation of tumor suppressor functions can effectively reverse the transformed phenotype and lead to cell cycle arrest or death of cancerous cells and be used as a therapeutic strategy. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease associated with infection of CD4 T cells by the Human T-cell Leukemia Virus Type 1 (HTLV-I). HTLV-I-associated T-cell transformation is the result of a multistep oncogenic process in which the virus initially induces chronic T-cell proliferation and alters cellular pathways resulting in the accumulation of genetic defects and the deregulated growth of virally infected cells. This review will focus on the current knowledge of the genetic and epigenetic mechanisms regulating the inactivation of tumor suppressors in the pathogenesis of HTLV-I.

scholarly journals Inactivation of X-linked tumor suppressor genes in human cancer

2012 ◽  
Vol 8 (4) ◽  
pp. 463-481 ◽  
Author(s):  
Runhua Liu ◽  
Mandy Kain ◽  
Lizhong Wang
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Human Cancer ◽  
Suppressor Genes

scholarly journals ei24, a p53 Response Gene Involved in Growth Suppression and Apoptosis

2000 ◽  
Vol 20 (1) ◽  
pp. 233-241 ◽  
Author(s):  
Zhengming Gu ◽  
Cathy Flemington ◽  
Thomas Chittenden ◽  
Gerard P. Zambetti
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Apoptotic Cell ◽  
Functional Characterization ◽  
Growth Control ◽  
P53 Tumor Suppressor ◽  
Cycle Arrest ◽  
P53 Response

ABSTRACT DNA damage and/or hyperproliferative signals activate the wild-type p53 tumor suppressor protein, which induces a G1 cell cycle arrest or apoptosis. Although the mechanism of p53-mediated cell cycle arrest is fairly well defined, the p53-dependent pathway regulating apoptosis is poorly understood. Here we report the functional characterization of murine ei24 (also known asPIG8), a gene directly regulated by p53, whose overexpression negatively controls cell growth and induces apoptotic cell death. Ectopic ei24 expression markedly inhibits cell colony formation, induces the morphological features of apoptosis, and reduces the number of β-galactosidase-marked cells, which is efficiently blocked by coexpression of Bcl-XL. Theei24/PIG8 gene is localized on human chromosome 11q23, a region frequently altered in human cancers. These results suggest that ei24 may play an important role in negative cell growth control by functioning as an apoptotic effector of p53 tumor suppressor activities.

scholarly journals Oncogenes - the basics

2018 ◽  
Vol 3 (4) ◽  
pp. 35-37
Author(s):  
Arnab Ghosh ◽  
Diasma Ghartimagar ◽  
Sushma Thapa
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Repair ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Normal Cell ◽  
Tumor Formation ◽  
Precursor Cell ◽  
Single Precursor ◽  
Normal Cell Cycle

Normal cell cycle and cell proliferation are regulated by several genes which can be broadly classified into 4 groups viz, proto-oncogenes, tumor suppressor genes, genes regulating apoptosis and genes involved in DNA repair. These genes may be defective due to different factors. The defective genes may lead to production of abnormal proteins which may lead to disruption of the normal cell cycle and proliferation. A single precursor cell with defective gene proliferates surpassing the normal physiologic regulatory process and leads to tumor formation, so, traditionally,it is said that “tumors are clonal”.

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