Activation Of Cell Cycle Arrest Research Articles

α-pinene regulates miR-221 and induces G2/M phase cell cycle arrest in human hepatocellular carcinoma cells.

The naturally occurring compound α-pinene induces cell cycle arrest and antitumor activity. We examined effects of α-pinene on cell cycle regulation in hepatocellular carcinoma cells (HepG2) cells to establish a foundation for its development as a novel treatment for hepatocellular carcinoma (HCC). HepG2 cells treated with α-pinene exhibited dose-dependent growth inhibition as a result of G2/M-phase cell cycle arrest. Cell cycle arrest was associated with down-regulated cyclin-dependent kinase 1 (CDK1) and miR-221 levels and up-regulated levels of CDKN1B/p27, γ-H2AX, phosphorylated ATM, phosphorylated Chk2 and phosphorylated p53. Our observations are consistent with a model in which α-pinene inhibits miR221 expression, which leads to G2/M-phase arrest and activation of CDKN1B/p27-CDK1 and ATM-p53-Chk2 pathways that suppress human hepatoma tumor progression. Additionally, α-pinene was found to trigger oxidative stress and induce apoptosis of HepG2 cells. α-pinene, therefore, represents a potential chemotherapeutic compound for the treatment of HCC.

Triptonide inhibits human nasopharyngeal carcinoma cell growth via disrupting Lnc-RNA THOR-IGF2BP1 signaling

Advanced stage nasopharyngeal carcinoma (NPC) has a poor prognosis. Triptonide (“TN”) is a small molecule monomer extract from the ancient Chinese herb Tripterygium wilfordii Hook. We show that TN, at nanomolar concentrations, potently inhibited survival and proliferation of multiple established and primary human NPC cells. TN induced NPC cell cycle arrest and apoptosis activation. NPC cell migration and invasion were also inhibited by TN. Importantly, TN was non-cytotoxic to nasopharyngeal epithelial cells. TN treatment in NPC cells disrupted LncRNA THOR (“Lnc-THOR”)-IGF2BP1 association, causing depletion of Lnc-THOR and downregulation of IGF2BP1 mRNA targets (Myc, IGF2 and Gli1). Lnc-THOR or IGF2BP1 knockout by CRISPR/Cas9 gene-editing methods mimicked and abolished TN's actions in NPC cells. Conversely, ectopic Lnc-THOR overexpression inhibited TN-induced cytotoxicity in NPC cells. Significantly, Lnc-THOR, IGF2BP1 and its mRNA targets are elevated in human NPC tissues and cells, but almost undetectable in nasopharyngeal epithelial tissues and cells. In vivo, intraperitoneal TN administration significantly inhibited subcutaneous NPC xenograft growth in mice. Similarly, Lnc-THOR-knockout HONE-1 xenografts grew significantly slower than control tumors. Thus, TN inhibits human NPC cell growth in vitro and in vivo via disrupting Lnc-THOR-IGF2BP1 signaling.

CNOT6L couples the selective degradation of maternal transcripts to meiotic cell cycle progression in mouse oocyte.

Meiotic resumption-coupled degradation of maternal transcripts occurs during oocyte maturation in the absence of mRNA transcription. The CCR4-NOT complex has been identified as the main eukaryotic mRNA deadenylase. In vivo functional and mechanistic information regarding its multiple subunits remains insufficient. Cnot6l, one of four genes encoding CCR4-NOT catalytic subunits, is preferentially expressed in mouse oocytes. Genetic deletion of Cnot6l impaired deadenylation and degradation of a subset ofmaternal mRNAs during oocyte maturation. Overtranslation of these undegraded mRNAs caused microtubule-chromosome organization defects, which led to activation of spindle assembly checkpoint and meiotic cell cycle arrest at prometaphase. Consequently, Cnot6l-/- female mice were severely subfertile. The function of CNOT6L in maturing oocytes is mediated by RNA-binding protein ZFP36L2, not maternal-to-zygotic transition licensing factor BTG4, which interacts with catalytic subunits CNOT7 and CNOT8 of CCR4-NOT Thus, recruitment of different adaptors by different catalytic subunits ensures stage-specific degradation of maternal mRNAs by CCR4-NOT This study provides the first direct genetic evidence that CCR4-NOT-dependent and particularly CNOT6L-dependent decay of selective maternal mRNAs is a prerequisite for meiotic maturation of oocytes.

Damaging and Defense Processes Induced in Plant Cells by UVB Radiation

UVB radiation (290–320 nm) activates various signaling mechanisms triggering the processes of programmed cell death in plants or their protection against the damaging action of this type of radiation. In the case of high dosages of UVB radiation, the mechanisms of cell death are associated with DNA damage and oxidative stress. In the first case, activation of DNA damage checkpoints and cell cycle arrest may occur; in the second case, cytochrome c is released from mitochondria with the subsequent activation of metacaspases. According to the existing data, both mechanisms induce DNA fragmentation and other changes typical for apoptotic cells, while low-intensity UVB radiation, which is perceived by a UVR8 photoreceptor, initiates protective processes promoting plant acclimatization to sunlight.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

In vitro behavior and UV response of melanocytes derived from carriers of CDKN2A mutations and MC1R variants.

Coinheritance of germline mutation in cyclin-dependent kinase inhibitor 2A (CDKN2A) and loss-of-function (LOF) melanocortin 1 receptor (MC1R) variants is clinically associated with exaggerated risk for melanoma. To understand the combined impact of these mutations, we established and tested primary human melanocyte cultures from different CDKN2A mutation carriers, expressing either wild-type MC1R or MC1RLOF variant(s). These cultures expressed the CDKN2A product p16 (INK4A) and functional MC1R. Except for 32ins24 mutant melanocytes, the remaining cultures showed no detectable aberrations in proliferation or capacity for replicative senescence. Additionally, the latter cultures responded normally to ultraviolet radiation (UV) by cell cycle arrest, JNK, p38, and p53 activation, hydrogen peroxide generation, and repair of DNA photoproducts. We propose that malignant transformation of melanocytes expressing CDKN2A mutation and MC1RLOF allele(s) requires acquisition of somatic mutations facilitated by MC1R genotype or aberrant microenvironment due to CDKN2A mutation in keratinocytes and fibroblasts.

Antitumor Activity of Diterpenoids from Jatropha gossypiifolia: Cell Cycle Arrest and Apoptosis-Inducing Activity in RKO Colon Cancer Cells.

Nine new minor diterpenoids, jatrogossones A-I (1-9), and six known analogues (10-15) were separated from an extract of the branches and leaves of Jatropha gosspiifolia. Compounds 4-6 and 10, possessing a 5/11 fused-ring skeleton, and 8, 9, and 13, with a 5/9/5 fused-ring skeleton, represent rare diterpenoid skeletons that have been found only in compounds isolated from plants of the Jatropha genus. The absolute configurations of 1-10 were defined by using a combination of electronic circular dichroism data analysis and single-crystal X-ray diffraction data. The cytotoxicity of the diterpenoids was evaluated using RKO and LOVO colon cancer cells in which regenerating islet-derived protein 3-alpha (Reg3A) is highly expressed. Compound 12 exhibited cytotoxicity against RKO colon cancer cells with an IC50 value of 2.6 μM. Morphological features of apoptosis and antimigration activities were evaluated in 12-treated RKO cells. Compound 12 effectively induced apoptosis of RKO, which was associated with G2/M-phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 12 significantly induced RKO cell apoptosis in a dose-dependent manner.

Design, synthesis and screening of 1, 2, 4-triazinone derivatives as potential antitumor agents with apoptosis inducing activity on MCF-7 breast cancer cell line

Some triazinone derivatives are designed and synthesized as potential antitumor agents. Triazinone derivatives 4c, 5e and 7c show potent anticancer activity over MCF-7 breast cancer cells higher than podophyllotoxin (podo) by approximate 6-fold. DNA flow cytometry analysis for the compounds 3c, 4c, 5e, 6c and 7c show a potent inhibitory activity of cell proliferation and cell cycle arrest at G2/M phase. Compounds 4c, 5e and 7c exhibit low to moderate β-tubulin polymerization inhibition percentage. Meanwhile, compound 6c displayed excellent β-tubulin percentage of polymerization inhibition equivalent to that exhibited by podo. In addition, compounds 4c, 5e and 7c show strong topoisomerase (topo) II inhibitory activity in nano-molar concentration, compared to known topo inhibitor as etoposide. Finally, apoptotic inducing activity over MCF-7 of compounds 4c, 5e, 6c and 7c is due to up-regulation of p53, increased Bax/Bcl-2 ratio and caspase3/7 levels 2-fold higher than podo.

Abstract 4309: SPCIP2 enhances breast cancer cell proliferation, cell cycle and tumor formation by expression and interaction with Y1

Abstract SPCIP2 is a member of the serine/threonine protein kinase family. However, the working mechanism of SPCIP2 in cellular functions has not yet been properly understood. In this study, we found that SPCIP2 directly interacts with Y1, a multifunctional protein that can act as a regulator of transcription and translation. Furthermore, we determined the binding domains required for the interaction between SPCIP2 and Y1. The ectopic expression of SPCIP2 activates cell growth by inducing Y1. Binding activates is confirmed by SPCIP2-dependent increase of Y1 expression, as well as by the induced cell proliferation and tumor formation. Also, expression of siSPCIP2 and siY1 is found to induce cell cycle arrest and apoptotic activity in breast cancer cells. These insights provide evidence that SPCIP2 induces cell proliferation and tumor formation via expression and interaction with Y1. Citation Format: Hyunjung Byun, Changhoon Lee. SPCIP2 enhances breast cancer cell proliferation, cell cycle and tumor formation by expression and interaction with Y1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4309.

RGNNV-induced cell cycle arrest at G1/S phase enhanced viral replication via p53-dependent pathway in GS cells

Nervous necrosis virus (NNV) is a ubiquitous pathogen in the aquaculture worldwide. Little is known about the relationship between NNV virus and host cells. Our studies showed that RGNNV infection could induce cell cycle arrest via activation of p53 signaling in cultured host cells. Infection of RGNNV redistributed NPM1, stabilized p53 and inhibited cell proliferation by inducing G1 arrest. RGNNV infection also led to phosphorylation and accumulation of p53 in a time-dependent manner. Furthermore, RGNNV infection upregulated cyclin-dependent kinase inhibitor 1 A (p21) and downregulated cyclin E and cyclin-dependent kinase 2 (CDK2). The expression of genes in the p53 pathway did not change significantly after p53 knockdown by pifithrin-α during RGNNV infection. However, NPM1 knockdown could abrogate RGNNV-induced cell proliferation inhibition, activation of p53 signaling and cell cycle arrest. In addition, RGNNV infection of the cells synchronized in various stages of cell cycle showed that viral genomic RNA and virus titer were higher in the cells released from G1 phase- or S phase-synchronized cells than that in the cells released from the G2 phase-synchronized or asynchronous cells after 18 h p.i. Therefore, our study reveals that RGNNV infection induces the p53-dependent pathway, resulting in a cell cycle arrest at G1 phase in host cells, which might provide a favorable condition for viral replication.

Construction and biological evaluation of different self-assembled nanoarchitectures of FZU-03,010

Chemotherapy is currently one of the promising therapeutic methods for non-small-cell lung cancer (NSCLC), but the emergence of multidrug resistance (MDR) is the greatest obstacle to efficient drug delivery for successful chemotherapy. Nanotechnology-based drug delivery holds great promise to promote intracellular drug delivery to reverse MDR. In this work, we used our previously synthesized ursolic acid (UA) derivative, FZU-03,010 (F3), to prepare nanodrugs of F3 with different architectures and study the role of the structure on the physiochemical properties and the biological effects against A549 and its PTX-resistant A549/PTX lung cancer cells. Using different preparation methods, amphiphilic F3 could self-assemble into different structures such as nanoaggregates (F3-NA), vesicles (F3-VC), or nanoparticles (F3-NP) with different physiochemical properties. The self-assembled nanodrugs could be utilized for the entrapment of fluorophores and showed different cellular uptake efficiencies. The cytotoxicity results demonstrated that compared with UA, F3-NA and F3-NP could suppress A549 and A549/PTX cells viability more potently at lower concentration. In addition, F3-NA and F3-NP could induce G1 cell cycle arrest, cell apoptosis and caspase-3 activation more efficiently than that of UA. Furthermore, F3-NA and F3-NP could effectively inhibit PI3K/Akt pathway and decrease the expression of Bcl-2 and the cell cycle-dependent kinase inhibitors p-ERK1/2 and Cyclin D1 in both A549 and A549/PTX cells. In conclusion, our results suggest that the UA derivative F3 is more potent in inhibiting cancer cell proliferation, and F3-NA and F3-NP have the potential to be developed as a therapeutic agent for resistant NSCLC cells.

Targeting Histone Deacetylases with Natural and Synthetic Agents: An Emerging Anticancer Strategy.

Cancer initiation and progression are the result of genetic and/or epigenetic alterations. Acetylation-mediated histone/non-histone protein modification plays an important role in the epigenetic regulation of gene expression. Histone modification is controlled by the balance between histone acetyltransferase and (HAT) and histone deacetylase (HDAC) enzymes. Imbalance between the activities of these two enzymes is associated with various forms of cancer. Histone deacetylase inhibitors (HDACi) regulate the activity of HDACs and are being used in cancer treatment either alone or in combination with other chemotherapeutic drugs/radiotherapy. The Food and Drug Administration (FDA) has already approved four compounds, namely vorinostat, romidepsin, belinostat, and panobinostat, as HDACi for the treatment of cancer. Several other HDACi of natural and synthetic origin are under clinical trial for the evaluation of efficiency and side-effects. Natural compounds of plant, fungus, and actinomycetes origin, such as phenolics, polyketides, tetrapeptide, terpenoids, alkaloids, and hydoxamic acid, have been reported to show potential HDAC-inhibitory activity. Several HDACi of natural and dietary origin are butein, protocatechuic aldehyde, kaempferol (grapes, green tea, tomatoes, potatoes, and onions), resveratrol (grapes, red wine, blueberries and peanuts), sinapinic acid (wine and vinegar), diallyl disulfide (garlic), and zerumbone (ginger). HDACi exhibit their antitumor effect by the activation of cell cycle arrest, induction of apoptosis and autophagy, angiogenesis inhibition, increased reactive oxygen species generation causing oxidative stress, and mitotic cell death in cancer cells. This review summarizes the HDACs classification, their aberrant expression in cancerous tissue, structures, sources, and the anticancer mechanisms of HDACi, as well as HDACi that are either FDA-approved or under clinical trials.

VS-5584 as a PI3K/mTOR inhibitor enhances apoptotic effects of subtoxic dose arsenic trioxide via inhibition of NF-κB activity in B cell precursor-acute lymphoblastic leukemia

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway as a survival signaling cascade is a prominent feature of cancers such as acute lymphoblastic leukemia (ALL). In patients with B-cell precursor-ALL (BCP-ALL), the high activity of the pathway correlates with the weak response to anti-leukemic drugs and relapse as a result of downstream prosurvival pathway activation, such as nuclear factor kappa B (NF-κB). Recent targeted therapy (PI3K/mTOR inhibitors) in combination with a multifunctional conventional chemotherapeutic drug may be useful for treatment of BCP-ALL patients. In the current study, the potential of a subtoxic dose (0.2 μM) of arsenic trioxide (ATO) in combination with VS-5584 (a highly potent PI3K/mTOR dual inhibitor) was tested for blocking of the PI3K/Akt/mTOR pathway, inhibition of NF-κB activation and induction of apoptosis and cell-cycle arrest. The data indicate that VS-5584 as a PI3K/mTOR inhibitor inhibited cell proliferation and induced apoptosis in NALM-6 cells by means of NF-κB transcriptional activity suppression. This apoptotic process markedly increased 72 h after administration of the subtoxic dose of ATO. We also showed that concomitant treatment of VS-5584 and the subtoxic dose of ATO significantly inhibited phosphorylation of NF-κB inhibitor alpha (IκBα) and S6 ribosomal protein (S6) as the downstream proteins of the PI3K/Akt/mTOR pathway. Combining VS-5584 and a subtoxic dose of ATO also resulted in down expression of the NF-κB target genes involved in cell proliferation and survival. These results indicate that incorporation of VS-5584/ATO combination into BCP-ALL therapeutic protocols can improve treatment and the survival of patients.

Cell Cycle Arrest and Apoptosis Induction Activity of Nitidine Chloride on Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, characterized by distorted proliferation and development of myeloid cells and their precursors in the bone marrow. Nitidine chloride, a naturally occurring alkaloid, has been identified to possess antitumor activity. However, the effects of nitidine chloride on acute myeloid leukemia cells and its underlying mechanisms have not been elucidated. Here we investigated the cellular and molecular mechanism of the anti-leukemic effects of nitidine chloride. Nitidine chloride treatment for 48 consecutive hours exhibited a timedependent and dose-dependent growth inhibition activity against AML cells by inducing cell cycle arrest and apoptosis. Moreover, nitidine chloride downregulated Cyclin B1, CDK1 and Bcl-2, upregulated p27 and Bax, inactivated PARP, activated Caspase-3 in AML cells. We further demonstrated that growth inhibition activity of nitidine chloride in AML cells is partially via inhibiting the phosphorylation of AKT and ERK. In conclusion, our data suggest that nitidine chloride could be an effective therapeutic agent against AML via cell cycle arrest and apoptosis.

Genomic alterations during p53-dependent apoptosis induced by γ-irradiation of Molt-4 leukemia cells.

Molt-4 leukemia cells undergo p53-dependent apoptosis accompanied by accumulation of de novo ceramide after 14 hours of γ-irradiation. In order to identify the potential mediators involved in ceramide accumulation and the cell death response, differentially expressed genes were identified by Affymetrix Microarray Analysis. Molt-4-LXSN cells, expressing wild type p53, and p53-deficient Molt-4-E6 cells were irradiated and harvested at 3 and 8 hours post-irradiation. Human genome U133 plus 2.0 array containing >47,000 transcripts was used for gene expression profiling. From over 10,000 probes, 281 and 12 probes were differentially expressed in Molt-4-LXSN and Molt-4-E6 cells, respectively. Data analysis revealed 63 (upregulated) and 20 (downregulated) genes (>2 fold) in Molt-4-LXSN at 3 hours and 140 (upregulated) and 21 (downregulated) at 8 hours post-irradiation. In Molt-4-E6 cells, 5 (upregulated) genes each were found at 3 hours and 8 hours, respectively. In Molt-4-LXSN cells, a significant fraction of the genes with altered expression at 3 hours were found to be involved in apoptosis signaling pathway (BCL2L11), p53 pathway (PMAIP1, CDKN1A and FAS) and oxidative stress response (FDXR, CROT and JUN). Similarly, at 8 hours the genes with altered expression were involved in the apoptosis signaling pathway (BAX, BIK and JUN), p53 pathway (BAX, CDKN1A and FAS), oxidative stress response (FDXR and CROT) and p53 pathway feedback loops 2 (MDM2 and CDKN1A). A global molecular and biological interaction map analysis showed an association of these altered genes with apoptosis, senescence, DNA damage, oxidative stress, cell cycle arrest and caspase activation. In a targeted study, activation of apoptosis correlated with changes in gene expression of some of the above genes and revealed sequential activation of both intrinsic and extrinsic apoptotic pathways that precede ceramide accumulation and subsequent execution of apoptosis. One or more of these altered genes may be involved in p53-dependent ceramide accumulation.

α-Tocopherol succinate enhances pterostilbene anti-tumor activity in human breast cancer cells in vivo and in vitro.

Vitamin E (Vit. E) is considered an essential dietary nutrient for humans and animals. An enormous body of evidence indicates the biological and protective effects of Vit. E consumption. Tocopherol-associated protein (TAP) is a major tocopherol-binding protein affecting Vit. E stimulation and downstream signaling transduction. However, how Vit. E utilizes TAP as an anti-cancer mechanism remains unclear. Microarray analysis of signature gene profiles in breast cancer cells treated with α-tocopheryl succinate (α-TOS, a Vit. E isoform) resulted in cell cycle arrest and anti-cancer activity in breast cancer cells. Pterostilbene (PS), a natural dietary antioxidant found in blueberries, in combination with α-TOS synergistically maximized breast cancer cell growth inhibition by disrupting signal transduction, transcription factors and cell cycle proteins. In a xenograft mouse model, PS treatment with Vit. E inhibited breast tumor growth and cell invasion, which were evaluated using our recently developed circulating tumor cell (CTC) detection assay. Because dietary Vit. E and PS supplementation contributed to preventative and therapeutic effects in vitro and in vivo, this combination may benefit breast cancer therapy in the clinic.

Increased Phosphorylation of Ser-Gln Sites on SUPPRESSOR OF GAMMA RESPONSE1 Strengthens the DNA Damage Response in Arabidopsis thaliana.

The Arabidopsis thaliana transcription factor SUPPRESSOR OF GAMMA RESPONSE1 (SOG1) regulates hundreds of genes in response to DNA damage, and this results in the activation of cell cycle arrest, DNA repair, endoreduplication, and programmed cell death. However, it is not clear how this single transcription factor regulates each of these pathways. We previously reported that phosphorylation of five Ser-Gln (SQ) motifs in the C-terminal region of SOG1 are required to activate downstream pathways. In this study, we introduced Ser-to-Ala (AQ) substitutions in these five SQ motifs to progressively eliminate them and then we examined the effects on DNA damage responses. We found that all SQs are required for the full activation of SOG1 and that the expression level of most downstream genes changed incrementally depending on the number of phosphorylated SQ sites. Genes involved in DNA repair and cell cycle progression underwent stepwise activation and inhibition respectively as the number of phosphorylated SQ sites increased. Also, inhibition of DNA synthesis, programmed cell death, and cell differentiation were incrementally induced as the number of phosphorylated SQ sites increased. These results show that the extent of SQ phosphorylation in SOG1 regulates gene expression levels and determines the strength of DNA damage responses.

CELL CYCLE ARREST ACTIVITY OF LITSEA CUBEBA LOUR: HEARTWOOD AND FRUIT EXTRACTS AGAINST T47D BREAST CANCER CELLS

Objective: This study was carried out to investigate cell cycle arrest activity toward T47D cells of Litsea cubeba heartwoods and fruits extract.Methods: Dry extracts were prepared from dry-grounded heartwoods and fruits by cold maceration using n-hexane, ethylacetate, and ethanol solvent. Cytotoxic activity were measured by [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide] methods and interpreted with inhibitory concentration 50% (IC50) value. Cell cycle arrest was investigated by flowcytometry method.Results: IC50 values for each n-hexane, ethylacetate, and ethanol of L. cubeba heartwoods and fruits were 76.34±2.61; 67.52±2.45; 71.23±2.37; 75.59±3.24; 162.58±15.08; 63.70±2.67 μg/mL, respectively. Cell cycle arrest for ethylacetate extract of heartwoods and fruits were accumulated in G0/G1 phase (56.70% and 65.56%).Conclusion: These results suggest that L. cubeba heartwoods and fruits has cell cycle arrest activity.

78P - In vivo activation of mitochondrial pathway and cell cycle arrest through silymarin loaded iron nanoparticles as proficient nanocomplex system for triple negative breast cancer therapy

78P - In vivo activation of mitochondrial pathway and cell cycle arrest through silymarin loaded iron nanoparticles as proficient nanocomplex system for triple negative breast cancer therapy

The Role of MDM2 in Promoting Genome Stability versus Instability.

In cancer, the mouse double minute 2 (MDM2) is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival versus cell death is complex and dependent on levels of MDM2 isoforms, p53 status, and cellular context. Extensive investigations have demonstrated that MDM2 protein–protein interactions with p53 and other p53 family members (p63 and p73) block their ability to function as transcription factors that regulate cell growth and survival. Upon genotoxic insults, a dynamic and intricately regulated DNA damage response circuitry is activated leading to release of p53 from MDM2 and activation of cell cycle arrest. What ensues following DNA damage, depends on the extent of DNA damage and if the cell has sufficient DNA repair capacity. The well-known auto-regulatory loop between p53-MDM2 provides an additional layer of control as the cell either repairs DNA damage and survives (i.e., MDM2 re-engages with p53), or undergoes cell death (i.e., MDM2 does not re-engage p53). Furthermore, the decision to live or die is also influenced by chromatin-localized MDM2 which directly interacts with the Mre11-Rad50-Nbs1 complex and inhibits DNA damage-sensing giving rise to the potential for increased genome instability and cellular transformation.