Cyclin A1 is a p53-induced gene that mediates apoptosis, G2/ M arrest, and mitotic catastrophe in renal, ovarian, and lung carcinoma cells

Rivera, Armando; Mavila, Anil; Bayless, Kayla J.; Davis, George E.; Maxwell, Steve A.

doi:10.1007/s00018-006-5521-5

Cited by 58 publications

(52 citation statements)

References 53 publications

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“…As outlined above, cyclin A1 has been implicated in the regulation of numerous processes associated with tumorigenesis (19)(20)(21)39), and its overexpression in the myeloid lineage of transgenic mice leads to myeloid leukemia (25). We therefore hypothesized that cyclin A1 might, in part, mediate the ability of Six1 to transform mammary epithelial cells.…”

Section: Resultsmentioning

confidence: 97%

“…Interestingly, cyclin A1 is up-regulated by Six1 in breast cancer cell lines and is critical for the Six1-mediated increase in proliferation in these cells (15). Aside from controlling proliferation, cyclin A1 influences numerous other cellular processes including cell survival, DNA repair, and angiogenesis (19)(20)(21). Its role in these processes suggests that cyclin A1 misexpression could contribute to several tumorigenic phenotypes that are found in a spectrum of different tumors.…”

Section: Introductionmentioning

confidence: 99%

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Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation

Coletta

Christensen²,

Micalizzi³

et al. 2008

Cancer Research

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Homeoproteins are transcription factors that act as master regulators of development and are frequently dysregulated in cancers. During embryogenesis, the Six1 homeoprotein is essential for the expansion of precursor cell populations that give rise to muscle and kidney, among other organs. Six1 overexpression is observed in numerous cancers, resulting in increased proliferation, survival, and metastasis. Here, we investigate whether Six1 can play a causal role in mammary tumor initiation. We show that Six1 overexpression in MCF12A mammary epithelial cells promotes multiple properties associated with malignant transformation, including increased proliferation, genomic instability, and anchorageindependent growth. We further show that this transformation is dependent on up-regulation of its transcriptional target, cyclin A1, which is normally expressed in the embryonic mammary gland but dramatically reduced in the adult gland. Six1-transformed MCF12A cells are tumorigenic in nude mice, forming aggressive tumors that are locally invasive and exhibit peritumoral lymphovascular invasion. In human breast carcinomas, expression of Six1 and cyclin A1 mRNA correlate strongly with each other (P < 0.0001), and expression of Six1 and cyclin A1 each correlate with Ki67, a marker of proliferation (P < 0.0001 and P = 0.014, respectively). Together, our data indicate that Six1 overexpression is sufficient for malignant transformation of immortalized, nontumorigenic mammary epithelial cells, and suggest that the mechanism of this transformation involves inappropriate reexpression of cyclin A1 in the adult mammary gland. [Cancer Res 2008;68(7):2204-13]

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation

Coletta

Christensen²,

Micalizzi³

et al. 2008

Cancer Research

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“…Apoptotic cells were also identified by morphological criteria, which included cell blebbing, fragmented and shrunken nuclei, and apoptotic bodies. To examine and quantitate apoptotic nuclei, cells were fixed by paraformaldehyde on glass slides and stained with 4Ј,6-diamidino-2-phenylindole nuclear stain (0.5 g/ml) as described (32). Imaging and quantitation of apoptotic nuclei were performed with a Nikon TE2000 ultraviolet microscope using the MetaMorph Imaging System software (Molecular Devices Corp., Chicago IL).…”

Section: Methodsmentioning

confidence: 99%

14-3-3ζ Mediates Resistance of Diffuse Large B Cell Lymphoma to an Anthracycline-based Chemotherapeutic Regimen

Maxwell

Jaya

et al. 2009

Journal of Biological Chemistry

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Patients presenting with diffuse large B cell lymphoma (DLBCL) are treated with a standard anthracycline-based chemotherapeutic mixture consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Half of DLBCL patients will develop chemo-refractory tumors due to the emergence of CHOP-resistant DLBCL cells. We isolated DLBCL cells that were resistant to CHOP as a model system to investigate the molecular basis of CHOP resistance. Resistant cells emerged from CHOP-sensitive DLBCL populations after repeated cycles of on-off exposure to stepwise increased dosages of CHOP. A proteomic analysis of CHOP-sensitive and -resistant DLBCL cells identified the isoform of the 14-3-3 family as a differentially expressed protein. CHOP-sensitive cells showed reduced expression of 14-3-3 protein in the presence of high-dose CHOP relative to control cells. In contrast, CHOP-resistant cells expressed markedly higher levels of 14-3-3 regardless the presence of high-dose CHOP. Because 14-3-3 is known to exert anti-apoptotic influences and chemoresistance in lung, colon, and prostate carcinoma, we hypothesized that 14-3-3 promotes survival of DLBCL cells in CHOP. In support of our hypothesis, knockdown of 14-3-3 by small interfering RNA restored the sensitivity of resistant DLBCL to CHOP-induce apoptosis. In addition, 14-3-3 expression was highly up-regulated in a resected DLBCL lymph node relative to a normal lymph node by Western blot analysis. Furthermore, more than half of 35 DLBCL tissues showed elevated 14-3-3 expression relative to normal lymph tissue by immunohistochemical analysis. Our study implicates 14-3-3 in the pathogenesis of DLBCL and suggests a promising combination strategy with a 14-3-3 inhibitor for the treatment of refractory DLBCL.

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“…In the present study, we studied the association of methylation status and response to concurrent platinum-based chemotherapy and found that patients with low methylation had a favorable response to concurrent chemotherapy, which could be due to the fact that genes were activated by epigenetic alterations. It has been shown that WIF1 and SFRP1 are involved in Wnt/b-catenin signaling, which induces apoptosis and inhibits carcinoma cell growth, invasion, and angiogenesis (29,30), that UCHL1 inhibits carcinoma cell growth and induces apoptosis through activating the p14 ARF -p53 tumor-suppressive pathway (31), that RASSF1A involved in the RAS-mediated signaling pathways promotes apoptosis, cell-cycle arrest, and inhibits cell migration (32), that CCNA1 mediates apoptosis, G 2 -M arrest, and mitotic catastrophe in multiple cells (33), and that activation of TP73 promotes E2F-1-induced apoptosis (34). Transcriptional silencing of six genes by inappropriate promoter methylation involved in biologic pathways that confer aggressive behavior and facilitate tumor development or dissemination has been observed in our study, which may therefore reflect different biologic characteristics of NPC tumors and serve as predictors of response to anticancer agents.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Identification of a Methylation Gene Panel as a Prognostic Biomarker in Nasopharyngeal Carcinoma

Jiang

Liu

Chen

et al. 2015

Molecular Cancer Therapeutics

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DNA methylation, the best known epigenetic marker, can be used as a prognostic biomarker in many cancers. We examined DNA methylation status and survival in nasopharyngeal carcinoma (NPC) patients. Aberrant DNA-methylated genes in 24 NPC tissues and 24 noncancer nasopharyngitis biopsy tissues (NCNBT) were identified using Illumina 450K BeadChip. Correlations between DNA methylation and clinical outcomes were evaluated using bisulfite pyrosequencing in 454 NPC patients.Genome-wide methylation analysis demonstrated that NPC tissues had distinct DNA methylation patterns compared with NCNBT. Among all significant CpG sites, 2,173 CpG sites with b change ! 0.2 (1,880 hypermethylated, 293 hypomethylated) were identified (P < 0.05). A methylation gene panel comprising six hypermethylated genes was constructed with the average Z-score method. Patients in the training cohort with high methylation had poorer disease-free survival [DFS, HR, 2.26; 95% confidence interval (CI), 1.28-4.01; P, 0.005] and overall survival (OS, HR, 2.47; 95% CI, 1.30-4.71; P, 0.006) than those with low methylation. There were similar results in the validation (DFS, HR, 2.07; 95% CI, 1.17-3.67; P, 0.013; OS, HR, 1.83; 95% CI, 1.01-3.31; P, 0.046) and independent cohorts (DFS, HR, 1.94; 95% CI, 1.08-3.47; P, 0.026; OS, HR, 2.09; 95% CI, 1.10-3.98; P, 0.022). Analysis indicated that the methylation gene panel was an independent prognostic factor. Furthermore, patients with low methylation had a favorable response to concurrent chemotherapy with an improved DFS (P ¼ 0.045) and OS (P ¼ 0.031), whereas patients with high methylation did not benefit from concurrent chemotherapy. The six-hypermethylated gene panel was associated with poor survival in patients with NPC, demonstrating its potential usefulness as a prognostic biomarker to clinicians in NPC management.

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Cyclin A1 is a p53-induced gene that mediates apoptosis, G2/ M arrest, and mitotic catastrophe in renal, ovarian, and lung carcinoma cells

Cited by 58 publications

References 53 publications

Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation

Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation

14-3-3ζ Mediates Resistance of Diffuse Large B Cell Lymphoma to an Anthracycline-based Chemotherapeutic Regimen

Genome-Wide Identification of a Methylation Gene Panel as a Prognostic Biomarker in Nasopharyngeal Carcinoma

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