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)

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D, is a potent inhibitor of breast cancer cell growth. Although it is evident that 1,25(OH)2D3 inhibits growth of both estrogen receptor alpha-positive [ER alpha(+)] and -negative [ER alpha(-)] breast cancer cells, the cellular pathways contributing to these effects remain unclear. We studied the gene expression patterns in ER alpha(+) MCF-7 and ER alpha(-) MDA MB 231 human breast cancer cells following 1,25(OH)2D3 treatment, using cDNA expression arrays. Both cell lines showed a significant induction of the 1,25(OH)2D3-dependent 24-hydroxylase gene, a marker for the actions of 1,25(OH)2D3. In MCF-7 cells, 51 genes were up-regulated and 19 genes were down-regulated. The up-regulated genes encoded cell adhesion molecules, growth factors/modulators, steroid receptors/co-activators, cytokines, kinases and transcription factors. Of the up-regulated genes, 40% were implicated in cell cycle regulation and apoptosis and included cyclin G1 and cyclin I, p21-activated kinase-1 (PAK-1), p53, retinoblastoma like-2 [Rb2 (p130)], insulin-like growth factor binding protein-5 (IGFBP5) and caspases. Among the down-regulated genes were ER alpha, growth factors, cytokines and several kinases. Some of these results were confirmed by real-time PCR. In MDA MB 231 cells, 20 genes were up-regulated and 13 genes were down-regulated. Very few genes directly implicated in cell cycle regulation were up-regulated. The matrix metalloproteinases formed a major class of genes that were down-regulated in the MDA MB 231 cells. Seven genes were commonly up-regulated in both cell lines and these included transforming growth factor (TGFbeta2) and Rb2 (p130). In conclusion, the gene expression profiles of the two cell lines studied were different with a few overlapping genes suggesting that different cellular pathways might be regulated by 1,25(OH)2D3 to exert its growth inhibitory effects in ER alpha(+) and ER alpha(-) cells.
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PMID:Vitamin D growth inhibition of breast cancer cells: gene expression patterns assessed by cDNA microarray. 1288 98

Ink4 proteins inhibit the enzymatic activities of cyclin D-dependent kinases, thereby governing transcriptional programs that depend on the activities of the retinoblastoma protein and other retinoblastoma family members (p107 and p130). Mice lacking Ink4c and p53 spontaneously develop a broad spectrum of neoplasms, usually presenting with multiple tumors of different histological types and dying of cancer by 6 months of age. Whereas thymic lymphomas or pituitary tumors predominate in mice lacking p53 or Ink4c, respectively, animals lacking both genes develop many vascular tumors and also present with medulloblastomas not observed in the parental strains. Unlike p53, loss of the Arf tumor suppressor did not contribute to the appearance of vascular or cerebellar tumors. Vascular tumors ranged in severity from angiomas to hemangiosarcomas, some of which could be transplanted into immunocompromised mice. Intriguingly, loss of Ink4c but maintenance of at least one Ink4d allele was required for formation of medulloblastomas in p53-null mice. In situ hybridization revealed that, in newborn mice, Ink4c is detected in the pia mater and in an adjacent layer of rapidly dividing cells within the cerebellar external granule layer (EGL), whereas Ink4d is primarily expressed in Purkinje neurons. Because the pia mater and Purkinje cells sandwich the cerebellar EGL from which medulloblastomas are presumed to arise, Ink4 proteins might function in a cell-autonomous manner in governing neuronal cell cycle exit as well as in a non-cell-autonomous manner in controlling the production of diffusible mitogens and chemokines that influence postnatal development of the cerebellar EGL.
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PMID:Hemangiosarcomas, medulloblastomas, and other tumors in Ink4c/p53-null mice. 1450 Mar 77

Retinoblastoma 1 (pRb) and the related pocket proteins, retinoblastoma-like 1 (p107) and retinoblastoma-like 2 (p130) (pRb(f), collectively), play a pivotal role in regulating eukaryotic cell cycle progression, apoptosis, and terminal differentiation. While aberrations in the pRb-signaling pathway are common in human cancers, the consequence of pRb(f) loss in the mammary gland has not been directly assayed in vivo. We reported previously that inactivating these critical cell cycle regulators in divergent cell types, either brain epithelium or astrocytes, abrogates the cell cycle restriction point, leading to increased cell proliferation and apoptosis, and predisposing to cancer. Here we report that mouse mammary epithelium is similar in its requirements for pRb(f) function; Rb(f) inactivation by T(121), a fragment of SV40 T antigen that binds to and inactivates pRb(f) proteins, increases proliferation and apoptosis. Mammary adenocarcinomas form within 16 mo. Most apoptosis is regulated by p53, which has no impact on proliferation, and heterozygosity for a p53 null allele significantly shortens tumor latency. Most tumors in p53 heterozygous mice undergo loss of the wild-type p53 allele. We show that the mechanism of p53 loss of heterozygosity is not simply the consequence of Chromosome 11 aneuploidy and further that chromosomal instability subsequent to p53 loss is minimal. The mechanisms for pRb and p53 tumor suppression in the epithelia of two distinct tissues, mammary gland and brain, are indistinguishable. Further, this study has produced a highly penetrant breast cancer model based on aberrations commonly observed in the human disease.
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PMID:pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. 1496 29

Histone deacetylase (HDAC) inhibitors induce an intrinsic type of apoptosis in human papillomavirus (HPV)-positive cells by disrupting the mitochondrial transmembrane potential (deltapsim). Loss of deltapsim was only detected in E7, but not in E6 oncogene-expressing cells. HDAC inhibition led to a time-dependent degradation of the pocket proteins pRb, p107 and p130, releasing 'free' E2F-1 following initial G1 arrest. Inhibition of proteasomal proteolysis, but not of caspase activity rescued pRb from degradation and functionally restored its inhibitory effect on the cyclin E gene, known to be suppressed by pRb-E2F-1 in conjunction with HDAC1. Using siRNA targeted against p53, E2F-1 still triggered apoptosis by inducing the E2F-responsive proapoptotic alpha- and beta-isoforms of p73. These data may determine future therapeutic strategies in which HDAC inhibitors can effectively eliminate HPV-positive cells by an apoptotic route that does not rely on the reactivation of the 'classical' p53 pathway through a preceding shut-off of viral gene expression.
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PMID:HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway. 1507 64

Cysteine-rich protein 61 (Cyr61) is a growth factor-inducible, immediate-early gene that has multifaceted activities in various cancers. In a previous study, we found that Cyr61 inhibited the growth of the H520 and H460 non-small-cell lung cancer (NSCLC) cell lines. In further studies, we now report that p53 plays a pivotal role in Cyr61-dependent cellular growth arrest. Blocking Cyr61 with a Cyr61 antibody resulted in the downregulation of expression of p53 and p21, as well as partially reversing the growth suppression of H520-Cyr61 cells. Proliferation of NSCLC cell lines (NCI-H157, H125, H1299), having a mutant p53, were not suppressed by Cyr61. Inhibition of wild-type p53, by either human papilloma virus type 16 E6 or a dominant-negative p53, resulted in the rescue of the growth suppression mediated by Cyr61 in the H520-Cyr61 cells. The enhanced levels of p21WAF1 and p130/RB2, in the Cyr61-expressing H520-Cyr61 cells, were also inhibited by blocking p53 showing that p21 and p130 were induced by p53 in these cells. In addition, levels of both c-myc and beta-catenin increased in Cyr61 stably transfected H520 cells. Moreover, beta-catenin was translocated into the nucleus in these cells. Inhibition of c-myc expression in the H520-Cyr61 cells with antisense c-myc resulted in their decreased levels of p53. Transfecting cells with a dominant-negative T-cell factor (TCF4), the specific inhibitor of the beta-catenin/TCF4 complex, downregulated the expression of c-myc. Taken together, the data suggest that Cyr61 suppressed the growth of NSCLC cells by triggering a signal transduction pathway through beta-catenin. In this pathway, Cyr61 activated the beta-catenin/TCF4 complex, which promoted the expression of c-myc and the latter induced expression of p53, and p53 upregulated p21WAF1 and p130/RB2, resulting in growth arrest.
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PMID:Cyr61 suppresses the growth of non-small-cell lung cancer cells via the beta-catenin-c-myc-p53 pathway. 1507 66

Certain cells of the human retina are extremely sensitive to loss of function of the retinoblastoma tumor suppressor gene RB. Retinoblastomas develop early in life and at high frequency in individuals heterozygous for a germ-line RB mutation, and sporadic retinoblastomas invariably have somatic mutation in the RB gene. In contrast, retinoblastomas do not develop in Rb+/- mice. Although retinoblastoma is thought to have developmental origins, the function of Rb in retinal development has not been fully characterized. Here we studied the role of Rb in normal retinal development and in retinoblastoma using conditional Rb mutations in the mouse. In late embryogenesis, Rb-deficient retinas exhibited ectopic S-phase and high levels of p53-independent apoptosis, particularly in the differentiating retinal ganglion cell layer. During postnatal retinal development, loss of Rb led to more widespread retinal apoptosis, and adults showed loss of photoreceptors and bipolar cells. Conditional Rb mutation in the retina did not result in retinoblastoma formation even in a p53-mutant background. However, on a p107- or p130-deficient background, Rb mutation in the retina caused retinal dysplasia or retinoblastoma.
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PMID:Cell type-specific effects of Rb deletion in the murine retina. 1523 17

Survivin is a putative oncogene that is aberrantly expressed in cancer cells. It has been hypothesized to play a central role in cancer progression and resistance to therapy in diverse tumor types. Although some of the transcriptional processes regulating its expression have been established, the diversity of genes that may be controlling the levels of its expression in both normal cells as well as in cancer cells has not been fully explored. The most common genetically mutated pathways in human malignancies are the p53 tumor suppressor pathway and the RB/E2F pathway. Both of these pathways, when intact, provide essential checkpoints in the maintenance of normal cell growth and protect the cell from DNA damage. Using non-transformed embryonic fibroblasts, we provide evidence of a molecular link between the regulation of survivin transcription and the RB/E2F family of proteins. We demonstrate that both pRB and p130 can interact with the survivin promoter and can repress survivin transcription. We also show that the E2F activators (E2F1, E2F2, and E2F3) can bind to the survivin promoter and induce survivin transcription. Genetically modified cells that harbor deletions in various members of the RB/E2F family confirm our data from the wild-type cells. Our findings implicate several members of the RB/E2F pathway in an intricate mechanism of survivin gene regulation that, when genetically altered during the process of tumorigenesis, may function within cancer cells to aberrantly alter survivin levels and enhance tumor progression.
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PMID:Aberrant regulation of survivin by the RB/E2F family of proteins. 1527 87

We recently reported that the transcriptional coactivator and histone acetyltransferase p300 plays an important role in the G(1) phase of the cell cycle by negatively regulating c-myc and thereby preventing premature G(1) exit (Kolli, et al. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 4646-4651; Baluchamy, et al. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 9524-9529). Because p300 does not substitute for all CREB-binding protein (CBP) functions, we investigated whether CBP also negatively regulates c-myc and prevents premature DNA synthesis. Here, we show that antisense-mediated depletion of CBP in serum-deprived human cells leads to induction of c-myc and that such cells emerge from quiescence without growth factors at a rate comparable with that of p300-depleted cells. The CBP-depleted cells contained significantly reduced levels of the cyclin-dependent kinase inhibitor p21 and low levels of p107 and p130 (but not pRb) phosphorylation, suggesting that these factors, along with elevated levels of c-Myc, contribute to induction of DNA synthesis. Antisense c-Myc reversed the phosphorylation of p107 and p130 and the induction of S phase in CBP-depleted cells, indicating that up-regulation of c-myc is directly responsible for the induction of S phase. Furthermore, the serum-stimulated p300/CBP-depleted cells did not traverse beyond S phase, and a significant number of these cells died of apoptosis, which was not related to p53 levels. These cells also contained significantly higher levels of c-Myc compared with normal cells. When c-myc expression was blocked by antisense c-Myc, the apoptosis of the serum-stimulated CBP-depleted cells was reversed, indicating that high levels of c-Myc contribute to apoptosis. Thus, despite their high degree of structural and functional similarities, normal levels of both p300 and CBP are essential for keeping c-myc in a repressed state in G(1) and thereby preventing inappropriate entry of cells into S phase. In addition, both these proteins also provide important functions in coordinated cell cycle progression.
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PMID:Effects of depletion of CREB-binding protein on c-Myc regulation and cell cycle G1-S transition. 1552 69

Proteins controlling cell growth, differentiation, apoptosis, and oncogenic stress are often deregulated in tumor cells. However, whether such deregulations affect tumor behavior remains poorly understood in many tumor types. We recently showed that the urothelium-specific expression of activated H-ras and SV40 T antigen in transgenic mice produced two distinctive types of tumors strongly resembling the human superficial papillary tumors and carcinoma in situ of the bladder, respectively. Here we assessed the expression of a key set of cell cycle regulators in these mouse tumors and in a new transgenic line expressing a cyclin D1 oncogene in the urothelium. We found that urothelia of the wild-type and cyclin D1 transgenic mice exhibited a profile of cell cycle regulators found in quiescent (G(0)) cells, indicating that urothelium overexpressing the cyclin D1 (an 8-fold increase) is reminiscent of normal urothelium and remains slow-cycling. Low-grade superficial papillary tumors induced by activated H-ras had no detectable Rb family proteins (Rb, p107, and p130) and late cell cycle cyclins and kinases (cyclin A, E, and CDK1), but had increased level of p16, p53, and MDM2. These data suggest that the inactivation of the Rb pathway plays an important role in H-ras-induced superficial papillary tumors and that oncogenic H-ras can induce a compensatory activation of alternative tumor suppressor pathways. In contrast, carcinoma in situ of the bladder induced by SV40 T antigen had increased expression of cell cycle regulators mainly active in post-G(1) phases. The fact that phenotypically different bladder tumors exhibit different patterns of cell cycle regulators may explain why these tumors have different propensity to progress to invasive tumors. Our results indicate that the transgenic mouse models can be used not only for studying tumorigenesis but also for evaluating therapeutic strategies that target specific cell cycle regulators.
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PMID:Differential expression of cell cycle regulators in phenotypic variants of transgenically induced bladder tumors: implications for tumor behavior. 1573 97

In vitro expansion of chondrocytes for tissue-engineering applications is limited by forms of growth arrest known as quiescence and replicative senescence. At the molecular level cyclin-dependent kinase inhibitors (CDKIs) are involved in mediating growth arrest in the G1 phase of the cell cycle. Using ribonuclease protection assays and immunocytochemical staining methods, we quantitatively analyzed expression profiles of G1 cell cycle inhibitors at the mRNA and protein levels. These inhibitors included the CDKIs of the CIP/KIP family (p21CIP1 p27KIP1, and p57KIP2) and the INK4 family (p15INK4b, p16INK4a, p18INK4c, and p19INK4d) as well as the retinoblastoma protein-family (pRb, p107, and p130) and the tumor suppressor p53. Analysis was carried out in proliferating, quiescent, and senescent states of primary cultures of adult human nasoseptal chondrocytes. The most pronounced effect (p < 0.0001) between cultures in proliferation and cultures in growth arrest was an increased expression of the CDKIs p57KIP2 and p15INK4b for quiescent growth arrest, and of p16INK4a, p15INK4b, and p57KIP2 for senescent growth arrest. Thus, these cell cycle inhibitors represent potential candidates for selective intervention to promote cellular multiplication of chondrocytes undergoing in vitro expansion for tissue-engineering applications. Possible methods of modulation include the targeted elimination of specifically identified cell cycle inhibitors by antisense technologies.
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PMID:In vitro expansion of human nasoseptal chondrocytes reveals distinct expression profiles of G1 cell cycle inhibitors for replicative, quiescent, and senescent culture stages. 1573 62


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