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)

1Alpha,25(OH)2 vitamin D3 (1,25(OH)2D3) can induce differentiation of osteoblastic cells by arresting the cell cycle at G1. The p53-inducible gene, WAF1/Cip1, is one of the inhibitors of cyclin-dependent kinases and can inhibit the phosphorylation of retinoblastoma protein (pRB), thereby keeping pRB functionally active. Here we show that in a p53-null human osteoblastic osteosarcoma MG-63 cell line, 10 nM of 1,25(OH)2D3 completely inhibits cell growth and increases alkaline phosphatase activity, which suggests the induction of osteoblastic differentiation. We also found a p53-independent increase of WAF1/Cip1 mRNA and promoter activation by 1,25(OH)2D3. On the other hand, the expression and the promoter activity of the RB gene decreased after treatment with 1,25(OH)2D3 during the differentiation of MG-63 cells. Our results suggest that the p53-independent WAF1/Cip1 induction by 1,25(OH)2D3 is important for osteoblastic differentiation of MG-63 cells.
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PMID:p53-independent induction of WAF1/Cip1 is correlated with osteoblastic differentiation by vitamin D3. 971 36

We previously demonstrated a correlation between wild-type p53 expression and appearance of osteoblastic-specific differentiation characteristics, as evidenced by basal osteocalcin gene expression in a mouse osteosarcoma tumor. The study reported here further explored the possibility of p53's having a distinct transcription-activating role in bone differentiation, in addition to its proposed role in G1 arrest and apoptosis. ROS17/2.3 osteoblastic osteosarcoma cells were stably transfected with a plasmid containing wild-type p53 binding sequences fused to the chloramphenicol acetyltransferase reporter gene. These cells were used to determine the transactivating role of p53 in regulation of osteocalcin gene expression. We chose two conditions under which osteocalcin expression is known to be upregulated: exposure of osteoblastic cells to differentiation-promoting medium and to vitamin D3. Exposure of the transfected cells to differentiation-promoting medium produced an increase in p53 transactivating activity correlating with the appearance of osteocalcin expression after about 1 wk. Vitamin D3 treatment resulted in upregulation of osteocalcin activity without a corresponding change in p53 transactivation activity or expression. In separate experiments, we tested whether changes in osteocalcin expression accompanied changes in p53 activity under conditions of downregulation of cell proliferation mediated by inhibition of DNA synthesis. Hydroxyurea treatment was used to inhibit DNA synthesis and produce growth arrest in osteoblastic cells. Inhibition of osteoblast cell proliferation was associated with a fourfold increase in p53 transactivating activity and a transient increase in osteocalcin steady-state expression. These results demonstrated a close relationship between p53 and osteocalcin and suggested a regulatory role for wild-type p53 in the control of basal osteocalcin gene expression in osteoblasts.
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PMID:p53 transactivity during in vitro osteoblast differentiation in a rat osteosarcoma cell line. 1036 15

Osteosarcoma is a malignant tumor with heterogeneous features both in histological and biological aspects. We have established three tumorigenic cell lines, MMOS1, MMOS2, and MMOS3, from three independent tumors that developed in nude mice after the inoculation of MMC2, an osteoblast-like cell line derived from p53-/- mice. Expression patterns of the osteoblast-related genes showed a marked difference between MMOS2 and the other two cell lines, and were correlated well with the features of the original tumors, ranging from an osteoblastic osteosarcoma (MMOS2) to tumors with scarce or no osteoid formation (MMOS1 and MMOS3). The properties of malignant cells also varied in the three cell lines. MMOS1, which was the most serum-dependent in vitro, developed markedly larger tumors in vivo than the other two cell lines. MMOS3 showed the fastest growth in low-serum conditions and produced the largest number of colonies in soft agar, but did not develop lung metastases, whereas MMOS1 and MMOS2 developed lung metastases with a frequency of 30 and 50%. These data suggest that the biological activities in vivo do not necessarily reflect those in vitro. Because the three tumorigenic cell lines share MMC2 as a common precursor, our data showed an example that the heterogeneity of osteosarcoma was created by genetic alterations that took place during the transformation process of each tumor.
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PMID:Morphological and biological heterogeneity of three tumorigenic cell lines derived from a single p53-/- osteoblast-like cell line, MMC2. 1204 66

We have been subculturing a human mandible-derived osteosarcoma cell line (HOSM-2) for approximately 15 years, and have compared the characters of early generations, which did not exhibit tumorigenicity, to those in the later generations. The shape and doubling time of the cells did not change during long-term culture. The number of chromosomes, however, changed from 59-81 in the 6th generation (modal number: 70) to 54-59 (modal number: 56 and 57), and the chromosomal structure also changed. In addition, the cell line in the later generations showed tumorigenicity in nude mice, and Codon 306 of the p53 gene was mutated to a stop codon due to a point mutation. HOSM-2 cells expressed osteoblast markers, thus confirming them to be osteoblastic osteosarcoma cells. These results showed that changes in certain genes in the HOSM-2 cells led to tumorigenicity in nude mice following long-term culture. In addition, as a mandible-derived cell line with characteristics different from those of limb-derived osteosarcoma cell lines, HOSM-2 cells may be a valuable model for mandibular osteosarcoma and osteoblasts.
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PMID:Characterization of the human mandibular osteoblastic osteosarcoma cell line HOSM-2 after long-term culture. 1517 45

We have previously shown p53 to have a specific role in osteoblast differentiation by its ability to regulate expression of certain bone specific proteins. In this study, we show mineralized matrix formation in vivo to be directly related to the presence of wild type p53 in osteoblastic osteosarcoma cells. In order to further understand the importance of p53 in differentiation, we investigated the relationship between p53 and Bone Morphogenetic Proteins (BMPs) (BMP 1, 2, 3A, 3B (GDF-10), 4, 5, 6, 7, 8A and 8B) during osteoblast differentiation. The expression of several BMPs were tested using RNase Protection Assay in differentiating ROS17/2.8 osteoblastic osteosarcoma cells. The expression of BMPs 1, 2, 3a, 3b and 7 showed time dependent modulation during in vitro differentiation. In order to determine if p53 has a role in this process, we used a murine osteosarcoma cell line stably expressing a temperature sensitive p53. Cells were exposed to ascorbic acid and glycerophosphates to hasten in vitro osteoblast differentiation and maintained either at 32 or 37 degrees C for expression of the wild type or mutant p53 phenotype. The expression of BMP-2, BMP-4 and BMP-7 were modulated in a p53 dependent fashion. We were able to confirm the p53 dependency of BMP-2 independently by RT-PCR. While BMP-2 expression was evident in the presence of both wild type and mutant p53, regulated expression was seen only in cells expressing wild type p53. Transient over expression of wild type p53 did not result in the same BMP-2 response as stable expression showing that the presence of p53 may be important for an orderly development of osteoblast differentiation rather than a direct effect on gene expression. The functional relationship between p53 and these bone specific markers is discussed.
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PMID:Relationship of bone morphogenetic protein expression during osteoblast differentiation to wild type p53. 1599 55

Osteosarcoma is the most common primary cancer of bone and one that predominantly affects children and adolescents. Osteoblastic osteosarcoma represents the major subtype of this tumor, with approximately equal representation of fibroblastic and chondroblastic subtypes. We and others have previously described murine models of osteosarcoma based on osteoblast-restricted Cre:lox deletion of Trp53 (p53) and Rb1 (Rb), resulting in a phenotype most similar to fibroblastic osteosarcoma in humans. We now report a model of the most prevalent form of human osteosarcoma, the osteoblastic subtype. In contrast to other osteosarcoma models that have used Cre:lox mediated gene deletion, this model was generated through shRNA-based knockdown of p53. As is the case with the human disease the shRNA tumors most frequently present in the long bones and preferentially disseminate to the lungs; feature less consistently modeled using Cre:lox approaches. Our approach allowed direct comparison of the in vivo consequences of targeting the same genetic drivers using two different technologies, Cre:lox and shRNA. This demonstrated that the effects of Cre:lox and shRNA mediated knock-down are qualitatively different, at least in the context of osteosarcoma, and yielded distinct subtypes of osteosarcoma. Through the use of complementary genetic modification strategies we have established a model of the most common clinical subtype of osteosarcoma that was not previously represented and more fully recapitulated the clinical spectrum of this cancer.
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PMID:Modeling distinct osteosarcoma subtypes in vivo using Cre:lox and lineage-restricted transgenic shRNA. 2348 87

Osteosarcoma is one of the most common bone tumors. However, the genetic basis for its pathogenesis remains elusive. Here, we investigated the roles of Hedgehog (Hh) signaling in osteosarcoma development. Genetically-engineered mice with ubiquitous upregulated Hh signaling specifically in mature osteoblasts develop focal bone overgrowth, which greatly resembles the early stage of osteosarcoma. However, these mice die within three months, which prohibits further analysis of tumor progression. We therefore generated a mouse model with partial upregulated Hh signaling in mature osteoblasts and crossed it into a p53 heterozygous background to potentiate tumor development. We found that these mutant mice developed malignant osteosarcoma with high penetrance. Isolated primary tumor cells were mainly osteoblastic and highly proliferative with many characteristics of human osteosarcomas. Allograft transplantation into immunocompromised mice displayed high tumorigenic potential. More importantly, both human and mouse tumor tissues express high level of yes-associated protein 1 (Yap1), a potent oncogene that is amplified in various cancers. We show that inhibition of Hh signaling reduces Yap1 expression and knockdown of Yap1 significantly inhibits tumor progression. Moreover, long non-coding RNA H19 is aberrantly expressed and induced by upregulated Hh signaling and Yap1 overexpression. Our results demonstrate that aberrant Hh signaling in mature osteoblasts is responsible for the pathogenesis of osteoblastic osteosarcoma through Yap1 and H19 overexpression.
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PMID:Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression. 2414 83

The cellular microenvironment plays a relevant role in cancer development. We have reported that mesenchymal stromal/stem cells (MSCs) deficient for p53 alone or together with RB (p53(-/-)RB(-/-)) originate leiomyosarcoma after subcutaneous (s.c.) inoculation. Here, we show that intrabone or periosteal inoculation of p53(-/-) or p53(-/-)RB(-/-) bone marrow- or adipose tissue-derived MSCs originated metastatic osteoblastic osteosarcoma (OS). To assess the contribution of bone environment factors to OS development, we analyzed the effect of the osteoinductive factor bone morphogenetic protein-2 (BMP-2) and calcified substrates on p53(-/-)RB(-/-) MSCs. We show that BMP-2 upregulates the expression of osteogenic markers in a WNT signaling-dependent manner. In addition, the s.c. coinfusion of p53(-/-)RB(-/-) MSCs together with BMP-2 resulted in appearance of tumoral osteoid areas. Likewise, when p53(-/-)RB(-/-) MSCs were inoculated embedded in a calcified ceramic scaffold composed of hydroxyapatite and tricalciumphosphate (HA/TCP), tumoral bone formation was observed in the surroundings of the HA/TCP scaffold. Moreover, the addition of BMP-2 to the ceramic/MSC implants further increased the tumoral osteoid matrix. Together, these data indicate that bone microenvironment signals are essential to drive OS development.
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PMID:Bone environment is essential for osteosarcoma development from transformed mesenchymal stem cells. 2444 10

Introduction. We present the extremely rare case of a patient with three metachronous osteosarcomas within 22 years without evident pulmonary manifestation of disease 30 years after first diagnosis. Case Presentation. In 1983, a high-grade osteosarcoma of the left distal femur was diagnosed in an 18-year-old Caucasian male. He received rotationplasty accompanied by pre- and postoperative chemotherapy. Ten years later, an osteoblastic osteosarcoma occurred in TH12. En bloc resection and pre- and postoperative chemotherapy followed. In 2005, the patient developed another high-grade osteosarcoma in his right distal femur. Treatment included a wide resection and reconstruction with a tumour endoprosthesis as well as (neo)adjuvant chemotherapy. After the third tumour occurrence, cytogenetic and molecular genetic examinations (p53, rb1) were performed, showing a normal genetic pattern. Screening for metastases never showed clinical evidence of extraskeletal tumour manifestation. Discussion. In patients presenting metachronous osteosarcoma, identification of their lesions clonality (second primary tumour or metastases) could lead to a better understanding of tumour development and help to filter patients who need extended long-term followup due to a higher risk of late occurring sarcoma recurrence.
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PMID:Three Metachronous Osteosarcomas within 22 Years without Pulmonary Metastases: A Case Report and Review of the Literature. 2445 68

Osteosarcoma (OS) is the most common bone cancer in children and young adults. The etiology of osteosarcoma is currently unknown. Besides the predominant osteoblasts, the presence of cartilage forming chondrocytes within its tumor tissues suggests a role of chondrogenesis in osteosarcoma development. Runx2 is a master transcription factor both for osteoblast differentiation and for chondrocyte maturation. Interestingly, RUNX2 has been shown to directly interact with p53 and Rb1, two genes essential for osteosarcoma development in mice. However the in vivo relevance of Runx2 during osteosarcoma progression has not been elucidated. We have recently shown that targeting Runx2 expression in hypertrophic chondrocytes delays chondrocyte maturation. It has also been shown that osteoblast-specific deletion of p53 and Rb1 genes developed osteosarcoma in mice. Here, we report our recent research findings using these osteosarcoma mouse models as well as human osteosarcoma tissues. We have detected high-level RUNX2 expression in human osteoblastic osteosarcoma, while chondroblastic osteosarcoma is predominant with chondroid matrix. To minimize the effect of strain difference, we have backcrossed osterix-Cre mice onto congenic FVB/N genetic background. We also detected low-GC content (36%) in sequence around the floxed Rb1 gene and demonstrated that addition of BSA into the reaction system increases the efficiency of PCR genotyping of floxed Rb1 gene. Finally, we successfully generated multiple osteosarcoma mouse models with or without Runx2 transgenic background. These mice showed heterogeneous osteosarcoma phenotypes and marker gene expression. Characterization of these mice will facilitate understanding the role of Runx2 in osteosarcoma pathogenesis and possibly, for osteosarcoma treatment.
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PMID:Research findings working with the p53 and Rb1 targeted osteosarcoma mouse model. 2495 78


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