Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of retinoblastoma must be individualized. Most patients with unilateral, non-metastatic retinoblastoma can be cured with enucleation alone. In patients with histologic risk factors, adjuvant chemotherapy is recommended, with the addition of orbital radiation for patients with trans-scleral involvement or tumor present at the level of the cut end of the optic nerve. Patients with metastases require intensive chemotherapy and consolidation with autologous hematopoietic stem cell rescue. Patients with bilateral or multifocal disease represent a major challenge. Cure of the disease is the first priority, but the therapeutic approach also has to consider eye and vision preservation. The approach is conservative, and only eyes with very advanced disease are enucleated upfront. Patients are treated with chemotherapy and intensive focal treatments, with the aim of delaying or avoiding radiation therapy and enucleation. For patients with early intraocular stage (Reese-Ellsworth groups I-III and International Groups A-B), the two-drug combination of vincristine and carboplatin is recommended. Patients with more advanced intraocular disease (Reese-Ellsworth groups IV-V and International Groups C-D) require more intensive chemotherapy. Standard of care for these patients incorporates etoposide into the regimen. Effective agents with good intraocular penetration, such as topotecan, are being investigated. Because most failures are secondary to progression of the vitreous seeds, subconjunctival carboplatin is added in cases with poor response of the vitreous tumors. Patients must be monitored very closely, with examinations under anesthesia every 4 to 6 weeks, and focal treatments are applied during the procedure. These include cryotherapy for small anterior tumors, thermotherapy and laser photocoagulation for small posterior tumors, and brachytherapy for larger tumors. New treatment approaches under development include the refinement of periocular chemotherapy administration using slow-release devices, the use of suicide gene therapy with local delivery of the herpes simplex thyrosine kinase gene (followed by systemic administration of ganciclovir), and the development of small-molecule inhibitors of the MDMX-p53 interaction.
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PMID:Treatment of retinoblastoma: current status and future perspectives. 1758 9

Gene expression profiling of metastatic brain tumors from primary lung adenocarcinoma, using a 17k-expression array, revealed that 1561 genes were consistently altered. Further functional classification placed the genes into seven categories: cell cycle and DNA damage repair, apoptosis, signal transduction molecules, transcription factors, invasion and metastasis, adhesion, and angiogenesis. Genes involved in apoptosis, such as caspase 2 (CASP2), transforming growth factor-beta inducible early gene (TIEG), and neuroprotective heat shock protein 70 (Hsp70) were underexpressed in metastatic brain tumors. Alterations in Rho GTPases (ARHGAP26, ARHGAP1), as well as down-regulation of the metastasis suppressor gene KiSS-1 were noted, which may contribute to tumor aggression. Overexpression of the invasion-related gene neurofibromatosis 1 (NF1), and angiogenesis-related genes vascular endothelial growth factor-B (VEGF-B) and placental growth factor (PGF) was also evidenced. Brain-specific angiogenesis inhibitors 1 and 3 (BAI1 and BAI3) were underexpressed as well. Examination of cell-adhesion and migration-related genes revealed an increased expression of integrins and extracellular matrices collagen and laminin. The study also showed alterations in p53 protein-associated genes, among these increased gene expression of p53, up-regulation of Reprimo or candidate mediator of the p53-dependent G2-arrest, down-regulation of p53-regulated apoptosis-inducing protein 1 (p53AIP1), decreased expression of tumor protein inducible nuclear protein 1 (p53DINP1), and down-regulation of Mdm4 (MDMX). The results demonstrated that genes involved in adhesion, motility, and angiogenesis were consistently up-regulated in metastatic brain tumors, while genes involved in apoptosis, neuroprotection, and suppression of angiogenesis were markedly down-regulated, collectively making these cancer cells prone to metastasis.
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PMID:Gene expression profiling of metastatic brain cancer. 1761 51

The RING domain of MDM2 that is essential for its E3 ligase activity mediates binding to itself and its structural homologue MDMX. Whereas it has been reported that RING domain interactions are critical, it is not well understood how they affect the E3 ligase activity of MDM2. We report that the E3 ligase activity requires the RING domain-dependent complex formation. In vivo, MDM2 and MDMX hetero-RING complexes are the predominant form versus the MDM2 homo-RING complex. Importantly, the MDM2/MDMX hetero-RING complexes exhibit a greater E3 ligase activity than the MDM2 homo-RING complexes. Disruption of the binding between MDM2 and MDMX resulted in a marked increase in both abundance and activity of p53, emphasizing the functional importance of this heterocomplex in p53 control.
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PMID:RING domain-mediated interaction is a requirement for MDM2's E3 ligase activity. 1761 58

Persistent inhibition of telomerase induces a severe telomere shortening in human T-cell leukemia virus type-1-infected cells which signals a DNA double-strand break damage response, formation of telomere dysfunction-induced foci and activates the ATM pathway. In turn, activation of ATM and its downstream effectors led to an increased phosphorylation and acetylation on specific residues of p53 known to be involved in transcriptional activation. Disruption of Mdm2-p53 complexes coupled with increased proteasomal degradation of MDMX further enhanced reactivation of p53 transcription, ultimately leading to senescence of tumor cells. Induction of senescence in these T-cells was associated with an increased expression of p21, p16 and activation of GSK3beta. Our results support the cancer-aging model and demonstrate that the halt of aging in cancer cells can be reversed through reactivation of p53.
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PMID:Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells. 1770 7

The p53 tumor suppressor plays a key role in protection against malignant transformation. MDM2 and MDMX are important regulators of the transcriptional activity and stability of p53 by binding to its NH(2) terminus. Recent studies suggest that inhibition of both MDM2 and MDMX is necessary for robust activation of p53 in certain tumor cells. However, small-molecule MDM2 inhibitors such as Nutlin fail to inhibit MDMX despite significant homology between the two proteins. The therapeutic efficacy of such compounds may be compromised by MDMX overexpression. To evaluate the feasibility and biological effects of simultaneously disrupting p53 binding to MDM2 and MDMX, we used phage display to identify a novel peptide that can inhibit p53 interactions with MDM2 (IC(50) = 10 nmol/L) and MDMX (IC(50) = 100 nmol/L). Expression of a scaffold protein (thioredoxin) displaying this peptide sequence by adenovirus disrupts both MDM2 and MDMX interaction with p53, resulting in efficient p53 activation, cell cycle arrest, and apoptosis of tumor cells overexpressing MDM2 and MDMX. Intratumoral injection of the adenovirus also induces growth suppression of tumor xenografts in mice in a p53-dependent fashion. These results show the therapeutic potential of targeting both MDM2 and MDMX in cancer, and provide a novel structural motif for the design of potent p53 activators.
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PMID:Efficient p53 activation and apoptosis by simultaneous disruption of binding to MDM2 and MDMX. 1787 22

Retinoblastoma is the third most common form of cancer in infants, and metastatic retinoblastoma is lethal in approximately 90% of cases. Early detection and aggressive therapy has resulted in a 95% probability of survival for retinoblastoma patients in the United States. However, the United States only represents 3-4% of the retinoblastoma cases worldwide. The majority of children diagnosed with retinoblastoma each year live in developing countries where the probability of survival is closer to 50%. This difference in survival rates reflects poor early detection rates and limited resources for the aggressive therapy necessary to treat retinoblastoma and manage the side effects associated with broad-spectrum systemic chemotherapy in young children. In order to have the most significant impact on retinoblastoma treatment in the United States and worldwide, current efforts have focused on local delivery of targeted chemotherapy. In this review, we summarize recent data showing that the p53 pathway is inactivated in 75% of retinoblastoma patients due to extra copies of the MDM2 and MDMX genes. A small molecule inhibitor of MDM2 called nutlin-3 can induce p53-mediated cell death in retinoblastoma cells. Subconjunctival delivery of nutlin-3 in preclinical models of retinoblastoma confirmed the efficacy of this approach in vivo. The advantage of local application of targeted chemotherapeutic agents such as nutlin-3 is that greater intraocular drug concentrations can be achieved without the side effects associated with systemic broad-spectrum chemotherapy. We propose that subconjunctival administration of targeted chemotherapy may be the best treatment option for children with retinoblastoma in the United States and throughout the developing world because it provides greater tumor response without the costs and complications associated with current treatment protocols.
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PMID:Targeting MDM2 and MDMX in retinoblastoma. 1804 74

We have shown previously that MDM2 promotes the degradation of the cyclin-dependent kinase inhibitor p21 through a ubiquitin-independent proteolytic pathway. Here we report that the MDM2 analog, MDMX, also displays a similar activity. MDMX directly bound to p21 and mediated its proteasomal degradation. Although the MDMX effect was independent of MDM2, they synergistically promoted p21 degradation when coexpressed in cells. This degradation appears to be mediated by the 26S proteasome, as MDMX and p21 bound to S2, one of the subunits of the 19S component of the 26S proteasome, in vivo. Conversely, knockdown of MDMX induced the level of endogenous p21 proteins that no longer cofractionated with 26S proteasome, resulting in G(1) arrest. The level of p21 was low at early S phase but markedly induced by knocking down either MDMX or MDM2 in human cells. Ablation of p21 rescued the G(1) arrest caused by double depletion of MDM2 and MDMX in p53-null cells. These results demonstrate that MDMX and MDM2 independently and cooperatively regulate the proteasome-mediated degradation of p21 at the G(1) and early S phases.
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PMID:MDMX promotes proteasomal turnover of p21 at G1 and early S phases independently of, but in cooperation with, MDM2. 1808 87

MDMX is an important regulator of p53 transcriptional activity and stress response. MDMX overexpression and gene amplification are implicated in p53 inactivation and tumor development. Unlike MDM2, MDMX is not inducible by p53, and little is known about its regulation at the transcriptional level. We found that MDMX levels in tumor cell lines closely correlate with promoter activity and mRNA level. Activated K-Ras and insulin-like growth factor 1 induce MDMX expression at the transcriptional level through mechanisms that involve the mitogen-activated protein kinase and c-Ets-1 transcription factors. Pharmacological inhibition of MEK results in down-regulation of MDMX in tumor cell lines. MDMX overexpression was detected in approximately 50% of human colon tumors and showed strong correlation with increased extracellular signal-regulated kinase phosphorylation. Therefore, MDMX expression is regulated by mitogenic signaling pathways. This mechanism may protect normal proliferating cells from p53 but also hamper p53 response during tumor development.
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PMID:Regulation of MDMX expression by mitogenic signaling. 1817 9

MDM2, a ubiquitin E3-ligase of the RING family, has a key role in regulating p53 abundance. During normal non-stress conditions p53 is targeted for degradation by MDM2. MDM2 can also target itself and MDMX for degradation. MDMX is closely related to MDM2 but the RING domain of MDMX does not possess intrinsic E3-ligase activity. Instead, MDMX regulates p53 abundance by modulating the levels and activity of MDM2. Dimerization, mediated by the conserved C-terminal RING domains of both MDM2 and MDMX, is critical to this activity. Here we report the crystal structure of the MDM2/MDMX RING domain heterodimer and map residues required for functional interaction with the E2 (UbcH5b). In both MDM2 and MDMX residues C-terminal to the RING domain have a key role in dimer formation. In addition we show that these residues are part of an extended surface that is essential for ubiquitylation in trans. This study provides a molecular basis for understanding how heterodimer formation leads to stabilization of MDM2, yet degradation of p53, and suggests novel targets for therapeutic intervention.
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PMID:Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. 1821 19

We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2-p53 interaction. MI-219 binds to human MDM2 with a K(i) value of 5 nM and is 10,000-fold selective for MDM2 over MDMX. It disrupts the MDM2-p53 interaction and activates the p53 pathway in cells with wild-type p53, which leads to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activates p53 in normal tissues with minimal p53 accumulation and is not toxic to animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.
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PMID:Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. 1831 39


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