Phenotypic alterations of small cell lung carcinoma induced by different levels of wild-type p53 expression

Adachi, Jun-ichi; Ookawa, Keizou; Tomizawa, Yoshio; Tsuchida, Shigeki; Yokota, Jun

doi:10.1038/sj.cdd.4400325

Cited by 17 publications

(14 citation statements)

References 33 publications

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“…In agreement with previous reports, the expression of p21 was induced by both high and low levels of p53 expression, but it did not appear to play a significant role in p53-induced apoptosis [23]. The cellular response to p53 activation may depend on not only the cell type, but also the levels of p53 expression [24,25]. Our results suggest that the level of p53 expression is important in determining cellular responses in terms of apoptosis or cell cycle arrest in Hep3B/tet/p53 cells.…”

Section: Discussionsupporting

confidence: 88%

Different levels of p53 induced either apoptosis or cell cycle arrest in a doxycycline-regulated hepatocellular carcinoma cell line in vitro

2006

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Induction of p53 gene expression in cancer cells can lead to both cell cycle arrest and apoptosis. To clarify whether the level of p53 expression determines the apoptotic response of hepatocellular carcinoma (HCC) cells, we assessed the effect of various levels of expression of p53 gene on a p53-deficient HCC cell line, Hep3B, utilizing a doxycycline (Dox)-regulated inducible p53 expression system. Our results showed that apoptosis was induced in HCC cells with high levels of p53 expression. However, lower level of p53 expression induced only cell cycle arrest but not apoptosis. Bax expression was up-regulated following high levels of p53 expression, while bcl-2 expression was not altered by the level of p53 expression. Moreover, p21 expression was observed in both high and low expression of p53. These results suggest the level of p53 expression could determine if the HCC cells would go into cell cycle arrest or apoptosis. Bax may participate, at least in part, in inducing p53-dependent apoptosis and the induction of p21 alone was able to cause cell cycle arrest but not apoptosis.

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Section: Discussionsupporting

confidence: 88%

Different levels of p53 induced either apoptosis or cell cycle arrest in a doxycycline-regulated hepatocellular carcinoma cell line in vitro

2006

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“…Such p53 cell speci®c dose-dependent responses have also been observed in the developing kidney (altered dierentiation) and in the lens (apoptosis induction) of other wtp53 transgenic models (Nakamura et al, 1995;Godley et al, 1996). They might be related to modulation of p53 functions: by expressing p53 in p53 null cell lines, lower levels of p53 result in growth arrest while higher levels induce apoptosis (Chen et al, 1996;Adachi et al, 1998). Furthermore, growth arrest is directly dependent on p53 transcription activity, which is not sucient to induce apoptosis.…”

Section: Organization In Syncytial Form Enhances the Consequences Of mentioning

confidence: 94%

Testicular wild-type p53 expression in transgenic mice induces spermiogenesis alterations ranging from differentiation defects to apoptosis

et al. 1999

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While p53 is dispensable for development, an excess of p53 has dramatic consequences on the embryogenesis and on the cell dierentiation. In an attempt to analyse in vivo the eects of p53 activity, we have generated transgenic mice expressing the wild-type p53 under the control of the metallothionein I promoter. In the three transgenic lines established, exogenous p53 is expressed constitutively in the postmeiotic cells of transgenic males and two lines are subfertile. Transgenic males expressing the upper level of p53 produce few spermatozoa since the majority of developing spermatids undergo apoptosis. In the subfertile males exhibiting an intermediate amount of p53, teratozoospermia is obvious suggesting an altered terminal dierentiation of postmeiotic cells. In contrast lower level of p53 does not lead the third line to sterility. These results suggest that the activity of p53 is dependent in vivo on the amount of p53 present within cells, as it has been already demonstrated in vitro.

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“…In fact, introduction of wild-type RB/ p16 or p53 induces growth arrest or apoptosis in lung cancer cells with inactivation of those genes. [8][9][10][11][12][13] In addition to genetic alterations disrupting the p53 and RB pathways, loss of heterozygosity (LOH) on chromosome 3p is frequently detected in both SCLC and NSCLC (~80%). 14) There are several candidate tumor suppressor genes inactivated by chromosome 3p LOH, including FHIT, RASSF1, and SEMA3B.…”

Section: Molecular Footprints Commonly Detected In Lung Cancer Cellsmentioning

confidence: 99%

Molecular footprints of human lung cancer progression

2004

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Lung cancer is the leading cause of cancer-related death in the world. To understand the molecular processes and pathways of, and contributing factors to lung cancer progression, genetic alterations in various progression stages of lung cancer cells have been studied, since these alterations can be regarded as molecular footprints representing the individual processes of multistage lung carcinogenesis. The results indicate that defects in both the p53 and RB/p16 pathways are essential for the malignant transformation of lung epithelial cells. Several other genes, such as Kras, PTEN and MYO18B, are genetically altered less frequently than p53 and RB/p16 in lung cancer cells, suggesting that alterations in these genes are associated with further malignant progression or unique phenotypes in a subset of lung cancer cells. everal genes are known to be genetically altered in human cancer cells. Most, if not all, of those alterations are considered as being critical for changing the phenotype of non-cancerous cells or cancer cells to more malignant ones by stepwise progression. Thus, genetic alterations responsible for each step of phenotypic change in the cells should be left in cancer cells as molecular footprints as long as the cells retain malignant phenotypes. Accordingly, the pathogenetic significance of each genetic alteration can be evaluated by analyzing the timing and specificity of the occurrence of the alteration during the course of cancer progression. In other words, the overall process of multistage human carcinogenesis is represented by accumulated genetic alterations (molecular footprints) in cancer cells. Since it is impossible to follow the process of accumulating genetic alterations in each cell in cancer patients, such molecular footprints are the most convincing evidence for understanding the process of multistage human carcinogenesis. Thus, if we could identify all the molecular footprints in cancer cells and correlate each of them with each specific phenotype of the cells, it would be possible to find novel ways of controlling malignant phenotypes of cancer cells in vivo at various stages in cancer patients.Molecular footprints considered in this paper include point mutation, deletion/insertion, amplification, and rearrangement in oncogenes and tumor suppressor genes, and they can be detected at the levels of single nucleotides, parts of or whole genes, and also segmental or whole chromosomes. Thus, for over the last two decades, molecular studies of human cancer have been focused on the identification of target oncogenes and tumor suppressor genes, which are activated and inactivated, respectively, with various types of molecular footprints in cancer cells. Tens to hundreds of oncogenes and tumor suppressor genes have already been identified, and the processes as well as pathways of multistage carcinogenesis have been discussed on the bases of accumulated genetic alterations in cancer cells. [1][2][3] Modes of genetic alterations are different among cancer cells, even though the same genes are...

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Phenotypic alterations of small cell lung carcinoma induced by different levels of wild-type p53 expression

Cited by 17 publications

References 33 publications

Different levels of p53 induced either apoptosis or cell cycle arrest in a doxycycline-regulated hepatocellular carcinoma cell line in vitro

Different levels of p53 induced either apoptosis or cell cycle arrest in a doxycycline-regulated hepatocellular carcinoma cell line in vitro

Testicular wild-type p53 expression in transgenic mice induces spermiogenesis alterations ranging from differentiation defects to apoptosis

Molecular footprints of human lung cancer progression

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