Key Roles for E2F1 in Signaling p53-Dependent Apoptosis and in Cell Division within Developing Tumors

Pan, Haiyan; Yin, Chaoying; Dyson, Nicholas J.; Ed, Harlow; Yamasaki, Lili; Dyke, Terry Van

doi:10.1016/s1097-2765(00)80273-7

Cited by 174 publications

(158 citation statements)

References 56 publications

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“…Studies have shown that ARF is not activated by DNA-damaging agents (24), rather by myc, ras, and E2F1 (24,37,38). Unregulated E2F1 activity induces ARF protein expression (37), which in turn stabilizes p53 and thus leads to cell cycle arrest and prevents uncontrolled cell proliferation (39,40). We found increased levels of E2F1 in our NSCLC cells overexpressing CTGF.…”

Section: Discussionmentioning

confidence: 74%

Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non–Small Cell Lung Cancer Cells

Chien¹,

Ding²,

Gui

et al. 2006

Molecular Cancer Research

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Connective tissue growth factor (CTGF) is a secreted protein that belongs to CCN family. The proteins in this family are implicated in various biological processes, such as angiogenesis, adhesion, migration, and apoptosis. In this study, we explored the roles of CTGF in lung tumorigenesis. The expression levels of CTGF in 58 lung cancer samples were reduced by >2 fold in 57% of the samples compared with matched normal samples using real-time reverse transcription-PCR. These results were confirmed by immunohistochemical staining for CTGF in normal lung epithelia and lung cancer. Cellular proliferation was inhibited in non -small cell lung cancer (NSCLC) cell lines NCI-H460, NCI-H520, NCI-H1299, and SK-MES-1 by CTGF overexpression. Partially purified CTGF suppressed lung cancer cell growth. The growth inhibition caused by CTGF overexpression was associated with growth arrest at G 0 -G 1 and prominent induction of p53 and ADP ribosylation factor. Most interestingly, overexpression of CTGF suppressed insulin-like growth factor-I -dependent Akt phosphorylation and epidermal growth factordependent extracellular signal-regulated kinase 1/2 phosphorylation. In summary, NSCLC cells expressed decreased levels of CTGF compared with normal lung cells; this lower expression has an effect on lung cancer cell proliferation and its cellular response to growth factors. Our data suggest that CTGF may behave as a secreted tumor suppressor protein in the normal lung, and its expression is suppressed in many NSCLCs.

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Section: Discussionmentioning

confidence: 74%

Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non–Small Cell Lung Cancer Cells

Chien¹,

Ding²,

Gui

et al. 2006

Molecular Cancer Research

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“…The concurrent disruption of growth control pathways may have implications in the cell cycle by abrogating the compensatory network that was proposed to exist between p53 and Rb1 pathways. According to this proposed model, loss of functional Rb results in deregulation of the E2F1, which in turn causes stabilization of p53, probably by activating the transcription of ARF (32,(47)(48)(49). Thus, if both pathways are disrupted and p27 is underexpressed, the control of cell proliferation might be profoundly impaired.…”

Section: Discussionmentioning

confidence: 99%

Low Expression of p27 Protein Combined with Altered p53 and Rb/p16 Expression Status Is Associated with Increased Expression of Cyclin A and Cyclin B1 in Diffuse Large B-Cell Lymphomas

Bai

Vlachonikolis

et al. 2001

Modern Pathology

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The expression of the cyclin-dependent kinase inhibitor (CDKI) p27 protein was investigated in relation to (1) the expression of the cell cycle regulators p53, Rb and p16 and (2) the proliferation profile as determined by the expression of Ki67, cyclin A, and cyclin B1 in 80 cases of de novo diffuse large B-cell lymphomas (DLBCL). P27 expression was low/null in large tumor cells in 58/80 cases and intermediate/high in 22/80 cases. Increased expression of p53 protein was observed in 39/80 cases. Decreased expression of Rb and p16 proteins was mutually exclusive and was observed in 5/80 and 14/80 cases, respectively. The analysis of the p27 expression status (low/null versus intermediate/high) with respect to the p53 and/or Rb/p16 expression status showed that low/null p27 expression was significantly correlated with increased p53 expression (P ‫؍‬ .018) and showed a strong trend for correlation with concurrent increased p53 expression and decreased Rb or p16 expression (P ‫؍‬ .050). These findings suggest a tendency for concurrent alterations of the cell cycle regulators p27, p53, and Rb or p16 in DLBCL, which might result in impaired tumor growth control. Indeed, the analysis of the combined p27/p53/ Rb/p16 expression status with respect to the proliferation profile showed that (1) three alterations in the combined p27/p53/Rb/p16 status (i.e., low/null P27 expression, increased expression of p53, and decreased expression of Rb or p16) were significantly correlated with increased expression of cyclin B1 (P ‫؍‬ .005) and (2) two or three alterations were significantly correlated with increased expression of cyclin A (P ‫؍‬ .014). These findings suggest combined impairment of a complex cell-cycle control network involving the CDK inhibitor p27, the P53 pathway, and the Rb1 pathway, which exerts a cooperative effect resulting in enhanced tumor cell proliferation.

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“…The ability of the E2F1 null background to reduce apoptosis in the lens tissue of Rb null mice demonstrated that previously reported p53-dependent apoptosis seen in the lens tissue of Rb null mice (Morgenbesser et al, 1994) could be due to the deregulated apoptotic function of E2F1 (Tsai et al, 1998) since E2F1 is the upstream regulator of the apoptotic function of p53 (Pan et al, 1998). Together, it is clear that E2F1 may act independently as well as upstream of p53 to induce apoptosis (Pan et al, 1998;Tsai et al, 1998). These ®ndings also suggest that the inhibitory activity of Rb on p53 mediated apoptosis could be mediated through E2F1.…”

Section: Introductionmentioning

confidence: 69%

mdm2: a bridge over the two tumour suppressors, p53 and Rb

et al. 1999

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The inactivation of the p53 and Rb pathways would account for the majority of human tumours. There are many levels of cross talk between p53 and Rb that have been identi®ed. However, the identi®cation of the mdm2-Rb interaction established a closer link between the two most well studied tumour suppressors, p53 and Rb. Recent studies of the novel trimeric complex Rb-mdm2-p53 provided us with a functional insight of how the two tumour suppressors can act together in regulating p53 induced apoptosis. Beginning with the properties of the Rb-mdm2-p53 trimeric complex, we shall review the propounding evidence suggesting that the apoptotic function of p53 is linked to its transrepression function. The uncoupling of the apoptotic function and transactivation function of p53 will also be discussed.

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Key Roles for E2F1 in Signaling p53-Dependent Apoptosis and in Cell Division within Developing Tumors

Cited by 174 publications

References 56 publications

Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non–Small Cell Lung Cancer Cells

Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non–Small Cell Lung Cancer Cells

Low Expression of p27 Protein Combined with Altered p53 and Rb/p16 Expression Status Is Associated with Increased Expression of Cyclin A and Cyclin B1 in Diffuse Large B-Cell Lymphomas

mdm2: a bridge over the two tumour suppressors, p53 and Rb

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