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

Mutations in p53 and reduced expression of the Cdk inhibitor p27Kip1 are frequently observed in a wide variety of human cancers, but it is not known whether alterations in these tumor suppressors interact to influence tumor progression. To address this, we measured tumor latency and spectrum in p53 and p27 single and compound mutant mice. p53-/- (null) mice developed T-cell lymphomas and soft-tissue sarcomas, while p27-/- mice developed adenomas of the pituitary and lung, but with much longer latency. The latency for tumor development in p53-/- p27-/- and p53-/- p27+/- compound mutant mice was significantly reduced, by 15-30%, compared to single mutant p53-/- mice. The tumor spectrum in the compound mutants was similar to that of p53-/- mice, and additional tumors of diverse histotypes. In tumors from p53-/- mice, p27 protein levels were reduced to a greater extent than were mRNA levels, indicating that p27 is downregulated in tumors at the transcriptional as well as post-transcriptional levels. In contrast, mice deficient in another Cdk inhibitor p21Cip1, which is also a transcriptional target and effector of p53, showed only a marginal increase in tumor predisposition in response to ENU treatment. Thus, downregulation of p27 is a common feature in p53-/- tumors. Germline deletion of one or both alleles of p27 accelerates tumor development and associated mortality in p53-/- mice, indicating potent synergy between loss of p27 and p53. Although p21 is functionally similar to both p53 and p27, it plays a lesser role in tumor suppression. These results further highlight the highly cooperative nature of p27 and its central role in tumor suppression.
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PMID:Distinct roles for p53, p27Kip1, and p21Cip1 during tumor development. 1464 11

To determine whether cellular aging leads to a cardiomyopathy and heart failure, markers of cellular senescence, cell death, telomerase activity, telomere integrity, and cell regeneration were measured in myocytes of aging wild-type mice (WT). These parameters were similarly studied in insulin-like growth factor-1 (IGF-1) transgenic mice (TG) because IGF-1 promotes cell growth and survival and may delay cellular aging. Importantly, the consequences of aging on cardiac stem cell (CSC) growth and senescence were evaluated. Gene products implicated in growth arrest and senescence, such as p27Kip1, p53, p16INK4a, and p19ARF, were detected in myocytes of young WT mice, and their expression increased with age. IGF-1 attenuated the levels of these proteins at all ages. Telomerase activity decreased in aging WT myocytes but increased in TG, paralleling the changes in Akt phosphorylation. Reduction in nuclear phospho-Akt and telomerase resulted in telomere shortening and uncapping in WT myocytes. Senescence and death of CSCs increased with age in WT impairing the growth and turnover of cells in the heart. DNA damage and myocyte death exceeded cell formation in old WT, leading to a decreased number of myocytes and heart failure. This did not occur in TG in which CSC-mediated myocyte regeneration compensated for the extent of cell death preventing ventricular dysfunction. IGF-1 enhanced nuclear phospho-Akt and telomerase delaying cellular aging and death. The differential response of TG mice to chronological age may result from preservation of functional CSCs undergoing myocyte commitment. In conclusion, senescence of CSCs and myocytes conditions the development of an aging myopathy.
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PMID:Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. 1500 38

CBP can function as a tumor suppressor, but the mechanisms that govern oncogenesis in its absence are unknown. Here we show that CBP inactivation in mouse thymocytes leads to lymphoma. Although CBP has been implicated in the transactivation functions of p53, development of these tumors does not seem to involve loss of p53 activity. CBP-null tumors show reduced levels of p27Kip1 and increased levels of cyclin E and Skp2, two oncoproteins that can promote p27Kip1 proteolysis. Reduction of p27Kip1 by introduction of a p27Kip1-null allele into CBP knockout mice accelerates lymphomagenesis and seems to obviate the requirement for Skp2 and cyclin E upregulation. These data suggest that CBP loss mediates lymphomagenesis in cooperation with a mechanism that reduces p27Kip1 abundance.
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PMID:Loss of CBP causes T cell lymphomagenesis in synergy with p27Kip1 insufficiency. 1499 93

Deregulation of apoptosis is involved in prostate cancer development and progression. This study involved an immunohistochemical "profiling" of prostate tissue specimens from patients who underwent prostatectomy for localized prostate cancer, to identify apoptosis-specific alterations associated with premalignant precursor lesions. Prostate tissue was pathologically evaluated, and areas of benign acini, high-grade prostate intraepithelial neoplasia (HGPIN), and prostate cancer were identified. Immunohistochemical analysis was performed to determine the expression of p27Kip1, a key cell cycle regulator, transforming growth factor (TGF)-beta receptor II (TbetaRII), a critical signaling effector of TGF-beta; Smad4, a downstream intracellular effector of TGF-beta signaling; p53, a key apoptosis regulator; and prostate-specific antigen (PSA), a clinical marker of prostate cancer. The apoptotic index of the same cell populations was determined using the transferase-mediated digoxigenin-tagged 16-desoxy-uridine-triphosphate nick end labeling assay. Our findings indicate a significant reduction in p27Kip1 immunoreactivity in HGPIN (P<0.0001) and prostate cancer (P<0.0001) compared with the benign tissue. A significant down-regulation was detected in TbetaRII expression in HGPIN and prostate cancer compared with benign prostatic hyperplasia (BPH)(P<0.001). A significant decrease was also observed in Smad4 levels in HGPIN and prostate cancer compared with BPH (P<0.001). Evaluation of the incidence of apoptosis revealed a significant decrease in the apoptotic index among the epithelial cell populations in HGPIN and a further decrease in prostate carcinoma (P<0.01). This reduced apoptotic index correlated with a significant increase in p53 immunoreactivity in the prostatic carcinoma foci. Prostate cancer cells exhibited strong nuclear staining for p53 compared with adjacent HGPIN (P<0.05) and the benign lesions of the same prostate specimens (P<0.05). A significant reduction in PSA immunostaining was detected in HGPIN and prostate carcinoma foci compared with the benign glandular epithelia (P<0.001). These results further define deregulation of TGF-beta signaling effectors as a molecular basis for loss of apoptotic control contributing to the development of prostate tumors. Identification of apoptotic regulators in precursor premalignant lesions may have prognostic significance in disease progression as well as therapeutic value for targeting prostate cancer.
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PMID:Apoptosis incidence and protein expression of p53, TGF-beta receptor II, p27Kip1, and Smad4 in benign, premalignant, and malignant human prostate. 1571 23

Many cell cycle regulatory proteins have been shown to be able to regulate cell death. Activation of Cdk2 has been shown to be necessary for the apoptosis of quiescent cells such as thymocytes, neurons, and endothelial cells. This activation is stimulus-specific because it occurs in glucocorticoid and DNA damage-induced but not in CD95-induced apoptosis in thymocytes. Apoptotic Cdk2 activation is controlled by apoptosis regulatory proteins like p53 and Bcl2 family members and correlates with degradation of its inhibitors p21Cip1 and p27Kip1 by activated caspases. Methods for measuring Cdk2 changes in activity in quiescent cells undergoing apoptosis are detailed in this chapter.
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PMID:Measurement of changes in apoptosis and cell cycle regulatory kinase Cdk2. 1510 61

Exposure of WI38 human diploid fibroblasts (HDFs) to hydrogen peroxide (H2O2) induced premature senescence. The senescent HDFs were permanently arrested and exhibited a senescent phenotype including enlarged and flattened cell morphology and increased senescence-associated beta-galactosidase (SA-beta-gal) activity. The induction of HDF senescence was associated with an activation of p53, increased expression of p21Cip1/WAF1, and hypophosphorylation of retinoblastoma protein (Rb), while no changes in the expression of p16Ink4a, p27Kip1, and p14Arf were observed. Exposure of WI38 cells to H2O2 also selectively activated phosphatidylinostol 3-kinase (PI3 kinase) and mitogen-activated protein kinase (MAPK) kinase (MEK), while no changes in p38 MAPK and Jun kinase (JNK) activities were observed. Selective inhibition of PI3 kinase activity with LY294002 abrogated H2O2-induced cell enlargement and flattened morphology and significantly attenuated the increase in SA-beta-gal activity, but did not affect H2O2-induced cell cycle arrest. In contrast, selective inhibition of MEK and p38 MAPK with PD98059 and SB203580, respectively, produced no significant effect on H2O2-induced senescent phenotype and cell cycle arrest. These findings demonstrate that expression of the senescent phenotype can be uncoupled from cell cycle arrest in prematurely senescent cells induced by H2O2 and does not contribute to the maintenance of permanent cell cycle arrest.
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PMID:Inhibition of phosphatidylinostol 3-kinase uncouples H2O2-induced senescent phenotype and cell cycle arrest in normal human diploid fibroblasts. 1524 73

Extracts of Artemisia asiatica Nakai (Asteraceae) possess anti-inflammatory and anti-oxidative activities. Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone), one of the pharmacologically active ingredients derived from A. asiatica, was shown to induce apoptosis in human promyelocytic leukemia (HL-60) cells [Mutat Res 496 (2001) 191]. In the present study, we examined the cytostatic effects of eupatilin in H-ras-transformed human breast epithelial (MCF10A-ras) cells. Eupatilin inhibited the growth of MCF10A-ras cells in a concentration-dependent and time-related manner. To explore whether the anti-proliferative effects of eupatilin could be mediated through modulation of the cell cycle in MCF10A-ras, DNA contents were analyzed by the flow cytometry. Eupatilin inhibited the expression of cyclin D1, cyclin B1, Cdk2 and Cdc2 that are key regulators of the cell cycle. In addition, eupatilin treatment led to elevated expression of p53 and p27Kip1 that act as Cdk inhibitors. It has been known that the Ras-signaling pathway plays integral roles in the induction of cyclin D1. Eupatilin inhibited the activation of ERK1/2 as well as expression of Raf-1 and Ras in MCF10A-ras cells. Thus, the inhibitory effect of eupatilin on cyclin D1 expression appears to be mediated by targeting the Raf/MEK/ERK signaling cascades. Eupatilin did not change activation of Akt, an important component of cell-survival pathways. In conclusion, the anti-proliferative effect of eupatilin in MCF10A-ras cells is associated with its blockade of cell cycle progression which appears to be attributable in part to inhibition of ERK1/2 activation.
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PMID:Eupatilin, a pharmacologically active flavone derived from Artemisia plants, induces cell cycle arrest in ras-transformed human mammary epithelial cells. 1531 4

The highly controlled degradation of proteins via the ubiquitin-proteasome pathway represents a key mechanism for cell regulation and homeostasis. Ubiquitin-dependent proteolysis, carried out in large part by the E3 ubiquitin ligases, is a critical mode of post-translational modification that is important in regulation of cell cycle progression, signal transduction, gene transcription, antigen receptor signaling, immune response and cell differentiation. Recent studies demonstrate that increasing numbers of proteins with ubiquitin ligase activity are being characterized. Identification and characterization of their substrates indicate that they regulate the turnover of key cell cycle proteins (p27Kip1, p21Cip1, p57Kip2, cyclin E), tumor suppressor proteins (p53, RB), signaling kinases (Src, Zap70, PI-3 kinase), apoptosis regulators (Bcl-2, Bax, Bik) and transcription factors (Myc, NF-kappaB, E1F1), all of which have been implicated in the pathogenesis of malignant lymphoma. Studies to determine the functional role of ubiquitin ligases in the pathogenesis of malignant lymphoma represent potential areas of investigation.
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PMID:Ubiquitin ligases in malignant lymphoma. 1535 30

We studied 159 cases of superficial (stage Ta or T1) bladder tumors to determine the significance on survival of a subset of regulators of transition from G1 to S phase of the cell cycle (p53, p21Waf1, p27Kip1, cyclin D1, cyclin D3) and tumor proliferation (Ki-67 [MIB-1]). Clinical findings (patient age, sex, tumor size, grade, stage [Ta or T1]) were included in the analysis. Univariate analysis revealed association of tumor size (P = .0353), grade in stage Ta tumors (P = .0074), cyclin D1 expression (P = .0182), and Ki-67 index (P = .0033) with disease-free survival and of tumor size (P = .0005), stage (P = .0494), cyclin D3 expression (P = .0105), and Ki-67 index (P = .0272) with overall survival. Cox multivariate analysis revealed cyclin D1 expression and high proliferation index (disease-free) and tumor size, cyclin D3 expression, and high proliferation index (overall survival) as independent predictors. Results suggest that alterations of the progression from the G1 to S phase of the cell cycle are common in papillary urothelial bladder tumors. High tumor proliferation, expression of cyclins D1 and D3, and tumor size at diagnosis might be relevant predictors of survival in patients with stage Ta and T1 bladder urothelial tumors.
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PMID:Prognostic factors in survival of patients with stage Ta and T1 bladder urothelial tumors: the role of G1-S modulators (p53, p21Waf1, p27Kip1, cyclin D1, and cyclin D3), proliferation index, and clinicopathologic parameters. 1536 77

Molecular markers have the potential to serve not only as prognostic factors but may be targets for new therapeutic strategies and predictors of response in a range of cancers. Prostate cancer development and progression is predicated on a series of genetic and epigenetic events within the prostate cell and its milieu. Within this review, we identify candidate molecules involved in diverse processes such as cell proliferation, death and apoptosis, signal transduction, androgen receptor (AR) signalling, cellular adhesion and angiogenesis that are linked to outcome in prostate cancer. Current markers with potential prognostic value include p53, Bcl-2, p16INK4A, p27Kip1, c-Myc, AR, E-cadherin and vascular endothelial growth factor. Evolving technology permits the identification of an increasing number of molecular markers with prognosis and predictive potential. We also review the use of gene microarray analysis in gene discovery as a means of identifying and cosegregating novel markers of prostate cancer outcome. By integrating selected markers into prospective clinical trials, there is potential for us to provide specific targeted therapy tailored for an increasing number of patients.
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PMID:Molecular markers of prostate cancer outcome. 1580 55


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