Inactivation Of MDM2 Research Articles

MDM2 provides TOP2 poison resistance by promoting proteolysis of TOP2βcc in a p53-independent manner

DNA topoisomerase II (TOP2) is an enzyme that performs a critical function in manipulating DNA topology during replication, transcription, and chromosomal compaction by forming a vital intermediate known as the TOP2-DNA cleavage complex (TOP2cc). Although the TOP2cc is often transient, stabilization can be achieved by TOP2 poisons, a family of anti-cancer chemotherapeutic agents targeting TOP2, such as etoposide (VP-16), and then induce double-strand breaks (DSBs) in cellular DNA. TOP2cc first needs to be proteolyzed before it can be processed by TDP2 for the removal of these protein adducts and to produce clean DNA ends necessary for proper repair. However, the mechanism by which TOP2βcc is proteolyzed has not been thoroughly studied. In this study, we report that after exposure to VP-16, MDM2, a RING-type E3 ubiquitin ligase, attaches to TOP2β and initiates polyubiquitination and proteasomal degradation. Mechanistically, during exposure to VP-16, TOP2β binds to DNA to form TOP2βcc, which promotes MDM2 binding and subsequent TOP2β ubiquitination and degradation, and results in a decrease in TOP2βcc levels. Biologically, MDM2 inactivation abrogates TOP2β degradation, stabilizes TOP2βcc, and subsequently increases the number of TOP2β-concealed DSBs, resulting in the rapid death of cancer cells via the apoptotic process. Furthermore, we demonstrate the combination activity of VP-16 and RG7112, an MDM2 inhibitor, in the xenograft tumor model and in situ lung cancer mouse model. Taken together, the results of our research reveal an underlying mechanism by which MDM2 promotes cancer cell survival in the presence of TOP2 poisons by activating proteolysis of TOP2βcc in a p53-independent manner, and provides a rationale for the combination of MDM2 inhibitors with TOP2 poisons for cancer therapy.

Identification of a small-molecule RPL11 mimetic that inhibits tumor growth by targeting MDM2-p53 pathway

BackgroundTargeting ribosome biogenesis to activate p53 has recently emerged as a therapeutic strategy in human cancer. Among various ribosomal proteins, RPL11 centralizes the nucleolar stress-sensing pathway by binding MDM2, leading to MDM2 inactivation and p53 activation. Therefore, the identification of MDM2-binding RPL11-mimetics would be valuable for anti-cancer therapeutics.MethodsBased on the crystal structure of the interface between RPL11 and MDM2, we have identified 15 potential allosteric modulators of MDM2 through the virtual screening.ResultsOne of these compounds, named S9, directly binds MDM2 and competitively inhibits the interaction between RPL11 and MDM2, leading to p53 stabilization and activation. Moreover, S9 inhibits cancer cell proliferation in vitro and in vivo. Mechanistic study reveals that MDM2 is required for S9-induced G2 cell cycle arrest and apoptosis, whereas p53 contributes to S9-induced apoptosis.ConclusionsPutting together, S9 may serve as a lead compound for the development of an anticancer drug that specifically targets RPL11-MDM2-p53 pathway.

E3 ubiquitin ligase MDM2 acts through p53 to control respiratory progenitor cell number and lung size.

The respiratory lineage initiates from the specification of NKX2-1+ progenitor cells that ultimately give rise to a vast gas-exchange surface area. How the size of the progenitor pool is determined and whether this directly impacts final lung size remains poorly understood. Here, we show that epithelium-specific inactivation of Mdm2, which encodes an E3 ubiquitin ligase, led to lethality at birth with a striking reduction of lung size to a single vestigial lobe. Intriguingly, this lobe was patterned and contained all the appropriate epithelial cell types. The reduction of size can be traced to the progenitor stage, when p53, a principal MDM2 protein degradation target, was transiently upregulated. This was followed by a brief increase of apoptosis. Inactivation of the p53 gene in the Mdm2 mutant background effectively reversed the lung size phenotype, allowing survival at birth. Together, these findings demonstrate that p53 protein turnover by MDM2 is essential for the survival of respiratory progenitors. Unlike in the liver, in which genetic reduction of progenitors triggered compensation, in the lung, respiratory progenitor number is a key determinant factor for final lung size.

BTK blocks the inhibitory effects of MDM2 on p53 activity.

p53 is a tumour suppressor that is activated in response to various types of stress. It is regulated by a complex pattern of over 50 different post-translational modifications, including ubiquitination by the E3 ligase MDM2, which leads to its proteasomal degradation. We have previously reported that expression of Bruton’s Tyrosine Kinase (BTK) induces phosphorylation of p53 at the N-terminus, including Serine 15, and increases its protein levels and activity. The mechanisms involved in this process are not completely understood. Here, we show that BTK also increases MDM2 and is necessary for MDM2 upregulation after DNA damage, consistent with what we have shown for other p53 target genes. Moreover, we found that BTK binds to MDM2 on its PH domain and induces its phosphorylation. This suggested a negative regulation of MDM2 functions by BTK, supported by the fact BTK expression rescued the inhibitory effects of MDM2 on p53 transcriptional activity. Indeed, we observed that BTK mediated the loss of the ubiquitination activity of MDM2, a process that was dependent on the phosphorylation functions of BTK. Our data together shows that the kinase activity of BTK plays an important role in disrupting the MDM2-p53 negative feedback loop by acting at different levels, including binding to and inactivation of MDM2. This study provides a potential mechanism to explain how BTK modulates p53 functions.

Ribosomopathy-like properties of murine and human cancers.

Ribosomopathies comprise a heterogeneous group of hematologic and developmental disorders, often characterized by bone marrow failure, skeletal and other developmental abnormalities and cancer predisposition. They are associated with mutations and/or haplo-insufficiencies of ribosomal proteins (RPs) and inefficient ribosomal RNA (rRNA) processing. The resulting ribosomal stress induces the canonical p19ARF/Mdm2/p53 tumor suppressor pathway leading to proliferative arrest and/or apoptosis. It has been proposed that this pathway is then inactivated during subsequent neoplastic evolution. We show here that two murine models of hepatoblastoma (HB) and hepatocellular carcinoma (HCC) unexpectedly possess features that mimic the ribosomopathies. These include loss of the normal stoichiometry of RP transcripts and proteins and the accumulation of unprocessed rRNA precursors. Silencing of p19ARF, cytoplasmic sequestration of p53, binding to and inactivation of Mdm2 by free RPs, and up-regulation of the pro-survival protein Bcl-2 may further cooperate to drive tumor growth and survival. Consistent with this notion, re-instatement of constitutive p19ARF expression in the HB model completely suppressed tumorigenesis. In >2000 cases of human HCC, colorectal, breast, and prostate cancer, RP transcript deregulation was a frequent finding. In HCC and breast cancer, the severity of this dysregulation was associated with inferior survival. In HCC, the presence of RP gene mutations, some of which were identical to those previously reported in ribosomopathies, were similarly negatively correlated with long-term survival. Taken together, our results indicate that many if not all cancers possess ribosomopathy-like features that may affect their biological behaviors.

Apoptosis of Sertoli cells after conditional ablation of murine double minute 2 (Mdm2) gene is p53-dependent and results in male sterility.

Beside its well-documented role in carcinogenesis, the function of p53 family has been more recently revealed in development and female reproduction, but it is still poorly documented in male reproduction. We specifically tested this possibility by ablating Mdm2, an E3 ligase that regulates p53 protein stability and transactivation function, specifically in Sertoli cells (SCs) using the AMH-Cre line and created the new SC-Mdm2−/− line. Heterozygous SC-Mdm2−/+ adult males were fertile, but SC-Mdm2−/− males were infertile and exhibited: a shorter ano-genital distance, an extra duct along the vas deferens that presents a uterus-like morphology, degenerated testes with no organized seminiferous tubules and a complete loss of differentiated germ cells. In adults, testosterone levels as well as StAR, P450c17 (Cyp17a1) and P450scc (Cyp11a1) mRNA levels decreased significantly, and both plasma LH and FSH levels increased. A detailed investigation of testicular development indicated that the phenotype arose during fetal life, with SC-Mdm2−/− testes being much smaller at birth. Interestingly, Leydig cells remained present until adulthood and fetal germ cells abnormally initiated meiosis. Inactivation of Mdm2 in SCs triggered p53 activation and apoptosis as early as 15.5 days post conception with significant increase in apoptotic SCs. Importantly, testis development occurred normally in SC-Mdm2−/− lacking p53 mice (SC-Mdm2−/−p53−/−) and accordingly, these mice were fertile indicating that the aforementioned phenotypes are entirely p53-dependent. These data not only highlight the importance of keeping p53 in check for proper testicular development and male fertility but also certify the critical role of SCs in the maintenance of meiotic repression.

Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation.

The central region of MDM2 is critical for p53 activation and tumor suppression. Upon ribosomal stress, this region is bound by ribosomal proteins, particularly ribosomal protein L11 (RPL11), leading to MDM2 inactivation and subsequent p53 activation. Here, we solved the complex structure of human MDM2-RPL11 at 2.4 Å. MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers. Formation of the MDM2-RPL11 complex induces substantial conformational changes in both proteins. RPL11, unable to bind MDM2 mutants, fails to induce the activation of p53 in cells. MDM2 mimics 28S rRNA binding to RPL11. The C4 zinc finger determines RPL11 binding to MDM2 but not its homolog, MDMX. Our results highlight the essential role of the RPL11-MDM2 interaction in p53 activation and tumor suppression and provide a structural basis for potential new anti-tumor drug development.

Tumor-specific signaling to p53 is mimicked by Mdm2 inactivation in zebrafish: insights from mdm2 and mdm4 mutant zebrafish.

In mice, the deletion of either Mdm2 or Mdm4 results in a p53-dependent embryonic lethality. We used zinc-finger nucleases to construct mutations in the mdm2 and mdm4 genes of zebrafish. Although the loss of mdm2 results in a p53-dependent early embryonic lethality, mdm4 mutant fish are viable and grow to adulthood. We also found that an in-frame five-amino acid deletion in mdm2 creates a novel hypomorphic allele. The lethal phenotype observed in the mdm2 mutant fish could be partially rescued by injecting mRNA encoding functional Mdm2, and this required the E3 ligase activity of the protein. Complete rescue was obtained by crossing the mdm2 mutant fish onto a p53M214K mutant background. Although p53 mutant fish on a wild-type mdm2 background were shown to accumulate high levels of p53 protein specifically in tumor tissues, we detected extensive staining of p53 in many normal tissues of the mdm2–p53M214K double-mutant fish. Our results are suggestive of the hypothesis that p53 protein accumulates during tumor formation as a result of tumor-specific inactivation of the Mdm2 pathway.

Epithelial cell-derived periostin functions as a tumor suppressor in gastric cancer through stabilizing p53 and E-cadherin proteins via the Rb/E2F1/p14ARF/Mdm2 signaling pathway

Periostin is usually considered as an oncogene in diverse human cancers, including breast, prostate, colon, esophagus, and pancreas cancers, whereas it acts as a tumor suppressor in bladder cancer. In gastric cancer, it has been demonstrated that periglandular periostin expression is decreased whereas stromal periostin expression is significantly increased as compared with normal gastric tissues. Moreover, periostin produced by stromal myofibroblasts markedly promotes gastric cancer cell growth. These observations suggest that periostin derived from different types of cells may play distinct biological roles in gastric tumorigenesis. The aim of this study was to explore the biological functions and related molecular mechanisms of epithelial cell-derived periostin in gastric cancer. Our data showed that periglandular periostin was significantly down-regulated in gastric cancer tissues as compared with matched normal gastric mucosa. In addition, its expression in metastatic lymph nodes was significantly lower than that in their primary cancer tissues. Our data also demonstrated that periglandular periostin expression was negatively associated with tumor stage. More importantly, restoration of periostin expression in gastric cancer cells dramatically suppressed cell growth and invasiveness. Elucidation of the mechanisms involved revealed that periostin restoration enhanced Rb phosphorylation and sequentially activated the transcription of E2F1 target gene p14ARF, leading to Mdm2 inactivation and the stabilization of p53 and E-cadherin proteins. Strikingly, these effects of periostin were abolished upon Rb deletion. Collectively, we have for the first time demonstrated that epithelial cell-derived periostin exerts tumor-suppressor activities in gastric cancer through stabilizing p53 and E-cadherin proteins via the Rb/E2F1/p14ARF/Mdm2 signaling pathway.

Mdm2 is required for maintenance of the nephrogenic niche

The balance between nephron progenitor cell (NPC) renewal, survival and differentiation ultimately determines nephron endowment and thus susceptibile to chronic kidney disease and hypertension. Embryos lacking the p53-E3 ubiquitin ligase, Murine double minute 2 (Mdm2), die secondary to p53-mediated apoptosis and growth arrest, demonstrating the absolute requirement of Mdm2 in embryogenesis. Although Mdm2 is required in the maintenance of hematopoietic stem cells, its role in renewal and differentiation of stem/progenitor cells during kidney organogenesis is not well defined. Here we examine the role of the Mdm2-p53 pathway in NPC renewal and fate in mice. The Six2-GFP::Cretg/+ mediated inactivation of Mdm2 in the NPC (NPCMdm2−/−) results in perinatal lethality. NPCMdm2−/− neonates have hypo-dysplastic kidneys, patchy depletion of the nephrogenic zone and pockets of superficially placed, ectopic, well-differentiated proximal tubules. NPCMdm2−/− metanephroi exhibit thinning of the progenitor GFP+/Six2+ population and a marked reduction or loss of progenitor markers Amphiphysin, Cited1, Sall1 and Pax2. This is accompanied by aberrant accumulation of phospho-γH2AX and p53, and elevated apoptosis together with reduced cell proliferation. E13.5–E15.5 NPCMdm2−/− kidneys show reduced expression of Eya1, Pax2 and Bmp7 while the few surviving nephron precursors maintain expression of Wnt4, Lhx1, Pax2, and Pax8. Lineage fate analysis and section immunofluorescence revealed that NPCMdm2−/− kidneys have severely reduced renal parenchyma embedded in an expanded stroma. Six2-GFP::Cretg/+; Mdm2f/f mice bred into a p53 null background ensures survival of the GFP-positive, self-renewing progenitor mesenchyme and therefore restores normal renal development and postnatal survival of mice. In conclusion, the Mdm2-p53 pathway is essential to the maintenance of the nephron progenitor niche.

AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy

The phosphatidylinositol 3-kinase (PI3K)/AKT and RAS oncogenic signalling modules are frequently mutated in sporadic human cancer. Although each of these pathways has been shown to play critical roles in driving tumour growth and proliferation, their activation in normal human cells can also promote cell senescence. Although the mechanisms mediating RAS-induced senescence have been well characterised, those controlling PI3K/AKT-induced senescence are poorly understood. Here we show that PI3K/AKT pathway activation in response to phosphatase and tensin homolog (PTEN) knockdown, mutant PI3K, catalytic, α polypeptide (PIK3CA) or activated AKT expression, promotes accumulation of p53 and p21, increases cell size and induces senescence-associated β-galactosidase activity. We demonstrate that AKT-induced senescence is p53-dependent and is characterised by mTORC1-dependent regulation of p53 translation and stabilisation of p53 protein following nucleolar localisation and inactivation of MDM2. The underlying mechanisms of RAS and AKT-induced senescence appear to be distinct, demonstrating that different mediators of senescence may be deregulated during transformation by specific oncogenes. Unlike RAS, AKT promotes rapid proliferative arrest in the absence of a hyperproliferative phase or DNA damage, indicating that inactivation of the senescence response is critical at the early stages of PI3K/AKT-driven tumourigenesis. Furthermore, our data imply that chronic activation of AKT signalling provides selective pressure for the loss of p53 function, consistent with observations that PTEN or PIK3CA mutations are significantly associated with p53 mutation in a number of human tumour types. Importantly, the demonstration that mTORC1 is an essential mediator of AKT-induced senescence raises the possibility that targeting mTORC1 in tumours with activated PI3K/AKT signalling may exert unexpected detrimental effects due to inactivation of a senescence brake on potential cancer-initiating cells.

Caveolar vesicles generate DNA damage and perpetuate cellular aging

Caveolar vesicles generate DNA damage and perpetuate cellular aging

NPM-ALK Modulates the p53 Tumour Suppressor Pathway in a JNK and PI 3-Kinase Dependent Manner: MDM-2 Is a Potential Therapeutic Target for the Treatment of ALK-Expressing Malignancies

Anaplastic large cell lymphoma (ALCL) is in the majority of cases a paediatric disease of a T- or null-cell phenotype and is characterised by the presence of the t(2;5)(p23;q35) or variant translocations involving the ALK gene on chromosome 2. This chromosomal translocation generates the Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) fusion protein, a hyperactive kinase with transforming properties. The p53 tumour suppressor gene is rarely mutated in ALK-expressing ALCL, perhaps one reason why this disease has a good prognosis. However, the mechanism controlling p53 activity in ALCL has not been fully elucidated. We show in patient-derived ALCL cell lines and NPM-ALK transformed BaF3 cells that NPM-ALK induces post-translational modification of the p53 antagonist MDM2, leading to inactivation of the p53 tumour suppressor pathway. Furthermore, we demonstrate that the PI 3-Kinase-Akt pathway downstream of NPM-ALK is responsible for this activity. It therefore follows that inactivation of MDM2 with the specific inhibitor nutlin-3 results in a decrease in proliferation and subsequently apoptosis of NPM-ALK-expressing ALCL cells, a response that is enhanced when cells are exposed to nutlin-3 in conjunction with the PI 3-Kinase inhibitor LY294003. We also demonstrate that NPM-ALK activates JNK by phosphorylation in turn leading to JNK-mediated sequestration and degradation of p53. This activity can be attenuated following administration of a specific JNK inhibitor. We conclude that NPM-ALK regulates the activity of the p53 tumour suppressor pathway via sequestration by JNK and MDM2 leading to its degradation. MDM2 antagonists in combination with JNK/PI 3-Kinase inhibitors may therefore be potential targets for the treatment of ALK-expressing malignancies such as ALCL.

NRH:Quinone Oxidoreductase 2 and NAD(P)H:Quinone Oxidoreductase 1 Protect Tumor Suppressor p53 against 20S Proteasomal Degradation Leading to Stabilization and Activation of p53

Tumor suppressor p53 is either lost or mutated in several types of cancer. MDM2 interaction with p53 results in ubiquitination and 26S proteasomal degradation of p53. Chronic DNA damage leads to inactivation of MDM2, stabilization of p53, and apoptotic cell death. Here, we present a novel MDM2/ubiquitination-independent mechanism of stabilization and transient activation of p53. The present studies show that 20S proteasomes degrade p53. The 20S degradation of p53 was observed in ubiquitin-efficient and -deficient cells, indicating that this pathway of degradation did not require ubiquitination of p53. The cytosolic quinone oxidoreductases [NRH:quinone oxidoreductase 2 (NQO2) and NAD(P)H:quinone oxidoreductase 1 (NQO1)] interacted with p53 and protected p53 against 20S proteasomal degradation. Further studies revealed that acute exposure to radiation or chemical leads to induction of NQO1 and NQO2 that stabilizes and transiently activates p53 and downstream genes. These results suggest that stress-induced NQO1 and NQO2 transiently stabilize p53, which leads to protection against adverse effects of stressors.

Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death

p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle cells (SMCs). Upon SMC-specific inactivation of mdm2, and not of mdm4, mice rapidly became ill and died. Necropsy showed small intestinal dilation, and histological analyses indicated a severe reduction in the number of intestinal SMCs. Increased p53 levels and activity were detected in the remaining SMCs, and the phenotype was completely rescued on a p53-null background. Interestingly, intestinal SMCs are caspase-3-negative and therefore did not undergo caspase-3-dependent apoptotic cell death. Together, Mdm2, but not Mdm4, prevents accumulation of active p53 in quiescent SMCs and thereby the induction of p53-mediated caspase-3-independent cell death.

Differential Regulation of Cardiomyocyte Survival and Hypertrophy by MDM2, an E3 Ubiquitin Ligase

MDM2 is an E3 ubiquitin ligase that regulates the proteasomal degradation and activity of proteins involved in cell growth and apoptosis, including the tumor suppressors p53 and retinoblastoma and the transcription factor E2F1. Although the effect of several MDM2 targets on cardiomyocyte survival and hypertrophy has already been investigated, the role of MDM2 in these processes has not yet been established. We have, therefore, analyzed the effect of overexpression as well as inhibition of MDM2 on cardiac ischemia/reperfusion injury and hypertrophy. Here we show that isolated cardiac myocytes overexpressing MDM2 acquired resistance to hypoxia/reoxygenation-induced cell death. Conversely, inactivation of MDM2 by a peptide inhibitor resulted in elevated p53 levels and promoted hypoxia/reoxygenation-induced apoptosis. Consistent with this, decreased expression of MDM2 in a genetic mouse model was accompanied by reduced functional recovery of the left ventricles determined with the Langendorff ex vivo model of ischemia/reperfusion. In contrast to cell survival, cell hypertrophy induced by the alpha-agonists phenylephrine or endothelin-1 was inhibited by MDM2 overexpression. Collectively, our studies indicate that MDM2 promotes survival and attenuates hypertrophy of cardiac myocytes. This differential regulation of cell growth and cell survival is unique, because most other survival factors are prohypertrophic. MDM2, therefore, might be a potential therapeutic target to down-regulate both cell death and pathologic hypertrophy during remodeling upon cardiac infarction. In addition, our data also suggest that cancer treatments with MDM2 inhibitors to reactivate p53 may have adverse cardiac side effects by promoting cardiomyocyte death.

Synergistic Tumor Suppression by Coexpression of FHIT and p53 Coincides with FHIT-Mediated MDM2 Inactivation and p53 Stabilization in Human Non-Small Cell Lung Cancer Cells

Aberrations of the tumor suppressor genes FHIT and p53 are frequently associated with a wide range of human cancers, including lung cancer. We studied the combined effects of FHIT and p53 proteins on tumor cell proliferation and apoptosis in human non-small cell lung carcinoma (NSCLC) cells in vitro and on tumor growth in animal models by adenoviral vector-mediated cotransfer of wild-type FHIT and p53 genes. We found that the coexpression of FHIT and p53 synergistically inhibited tumor cell proliferation in NSCLC cells in vitro and suppressed the growth of human tumor xenografts in nude mice. Furthermore, we found that this synergistic inhibition of tumor cell growth corresponded with the FHIT-mediated inactivation of MDM2, which thereby blocked the association of MDM2 with p53, thus stabilizing the p53 protein. Our results therefore reveal a novel molecular mechanism consisting of FHIT-mediated tumor suppression and the interaction of FHIT with other cellular components in the pathways regulating p53 activity. These findings show that combination treatment with synergistic tumor-suppressing gene therapy such as Ad-FHIT and Ad-p53 may be an effective therapeutic strategy for NSCLC and other cancers.

Regulation of p53: intricate loops and delicate balances.

The p53 tumor suppressor protein provides a major anti-cancer defense mechanism, as underscored by the fact that the p53 gene is the most frequent target for genetic alterations in human cancer. Recent work has led to the realization that p53 lies at the hub of a very complex network of signaling pathways that integrate a variety of intracellular and extracellular inputs. Part of this network consists of an array of autoregulatory feedback loops, where p53 exhibits very intricate interactions with other proteins known to play important roles in the determination of cell fate. We discuss two such loops, one involving the beta-catenin protein and the other centering on the Akt/PKB protein kinase. In both cases, the central module is the interplay between p53 and the Mdm2 protein, which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated beta-catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can promote the degradation and down-regulation of beta-catenin. Similarly, Akt can block p53 activation by potentiating Mdm2, whereas activated p53 can tune down Akt in several different ways. In each case, the actual output of the loop is determined by the delicate balance between the opposing effects of its different components. Often, this balance is dictated by additional signaling processes that occur simultaneously within the same cell. Genetic alterations characteristic of cancer are capable of severely distorting this balance, thereby overriding the tumor suppressor effects of p53 in a manner that facilitates neoplastic conversion.

RETRACTED: Regulation of p53: intricate loops and delicate balances

The p53 tumor suppressor protein provides a major anti-cancer defense mechanism, as underscored by the fact that the p53 gene is the most frequent target for genetic alterations in human cancer. Recent work has led to the realization that p53 lies at the hub of a very complex network of signaling pathways, which integrate a variety of intracellular and extracellular inputs. Part of this network consists of an array of autoregulatory feedback loops, where p53 exhibits very intricate interactions with other proteins known to play important roles in the determination of cell fate. We discuss two such loops, one involving the beta catenin protein and the other centering on the Akt/protein kinase B. In both cases, the central module is the interplay between p53 and the murine double minute 2 (Mdm2) protein, which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated beta catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can promote the degradation and downregulation of beta catenin. Similarly, Akt can block p53 activation by potentiating Mdm2, whereas activated p53 can tune down Akt in several different ways. In each case, the actual output of the loop is determined by the delicate balance between the opposing effects of its different components. Often, this balance is dictated by additional signaling processes that occur simultaneously within the same cell. Genetic alterations characteristic of cancer are capable of severely distorting this balance, thereby overriding the tumor suppressor effects of p53 in a manner that facilitates neoplastic conversion.

Conditional inactivation of Mdm2

Conditional inactivation of Mdm2