Astrocyte-specific expression of CDK4 is not sufficient for tumor formation, but cooperates with p53 heterozygosity to provide a growth advantage for astrocytes in vivo

Huang, Zhiyong; Baldwin, Rebecca L.; Hedrick, Nicolé M.; Gutmann, David H.

doi:10.1038/sj.onc.1205206

Cited by 21 publications

(14 citation statements)

References 31 publications

(37 reference statements)

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“…Cultured astrocytes from these mice do not demonstrate a cellautonomous growth advantage in vitro and lack properties of transformed cells. Interestingly, CDK4-overexpressing C6 glioma cell lines were found to exhibit increased cell growth (Huang et al, 2002). Even though CDK4 is coamplified with PIKE-A, our results demonstrate that PIKE-A overexpression alone is sufficient to elicit NIH3T3 cell transformation.…”

Section: Discussionmentioning

confidence: 64%

PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion

Liu

Hao

et al. 2007

Oncogene

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Section: Discussionmentioning

confidence: 64%

PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion

Liu

Hao

et al. 2007

Oncogene

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“…In cancer cells, the pRB brakes are often defective, resulting in E2F-dependent G 1 -S gene expression even in the absence of mitogens [14]. This may arise as a result of activating tumourigenic mutations which have been identified in diverse tumours at all levels in the mitogenic signalling pathways from ligands and receptors (eg HER2/ErbB2/neu receptor mutations or HER2 gene amplification) to downstream signalling networks (eg Ras-Raf-MAPK or PI3K-Akt signalling pathways) and also for the cell cycle-regulated genes themselves (eg CYCLIND1 and CDK4 gene amplification) [15][16][17]. Aberrant signalling promotes activation of CDK-cyclin complexes, which phosphorylate Rb and attenuate its capacity to induce transcriptional repression.…”

Section: Introductionmentioning

confidence: 99%

The cell cycle and cancer

Williams

Stoeber

2011

The Journal of Pathology

543

406

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Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.

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“…), while p21 CIP1/WAF1 -deficient 3T3 cells were a gift from Andrew Koff (Memorial Sloan Kettering Cancer Center, New York, N.Y.). Primary astrocyte cultures containing Ͼ97% glial fibrillary acidic protein-immunoreactive cells (astrocytes) were generated from day 2 postnatal pups as previously described (32).…”

Section: Methodsmentioning

confidence: 99%

T-Cadherin-Mediated Cell Growth Regulation Involves G₂ Phase Arrest and Requires p21^CIP1/WAF1 Expression

Huang

Hedrick

et al. 2003

Molecular and Cellular Biology

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Members of the cadherin family have been implicated as growth regulators in multiple tumor types. Based on recent studies from our laboratory implicating T-cadherin expression in mouse brain tumorigenesis, we examined the role of T-cadherin in astrocytoma growth regulation. In this report, we show that T-cadherin expression increased during primary astrocyte physiologic growth arrest in response to contact inhibition and serum starvation in vitro, suggesting a function for T-cadherin in astrocyte growth regulation. We further demonstrate that transient and stable reexpression of T-cadherin in deficient C6 glioma cell lines results in growth suppression. In addition, T-cadherin-expressing C6 cell lines demonstrated increased homophilic cell aggregation, increased cell attachment to fibronectin, and decreased cell motility. Cell cycle flow cytometry demonstrated that T-cadherin reexpression resulted in G 2 phase arrest, which was confirmed by mitotic index analysis. This growth arrest was p53 independent, as T-cadherin could still mediate growth suppression in p53 ؊/؊ mouse embryonic fibroblasts. T-cadherin-expressing C6 cell lines exhibited increased p21 CIP1/WAF1 , but not p27 Kip1 , expression. Lastly, T-cadherin-mediated growth arrest was dependent on p21 CIP1/WAF1 expression and was eliminated in p21 CIP1/WAF1 -deficient fibroblasts. Collectively, these observations suggest a novel mechanism of growth regulation for T-cadherin involving p21 CIP1/WAF1 expression and G 2 arrest.Astrocytomas are the most common primary malignant cancer affecting the nervous system, and despite aggressive therapy, the median survival of patients diagnosed with a highgrade astrocytoma (glioma) is only 9 to 12 months (35). These malignant glial tumors are hypothesized to develop as the result of the stepwise accumulation of specific genetic changes in astrocytes or astroglial precursors that promote astrocyte transformation and malignant progression (8). Genetic events important for astrocytoma formation and progression involve alterations in pathways involved in mitogenic signaling, cell cycle growth regulation, and environmental sensing. Previous studies have demonstrated that astrocytomas harbor changes in the epidermal and platelet-derived growth factor signaling pathways, involving amplification, mutation, or overexpression of these receptor tyrosine kinase molecules to result in increased mitogenic signaling. Similarly, astrocytomas harbor alterations in the p53 and retinoblastoma (Rb) cell cycle regulatory pathways. Inactivating mutations in the p53, p16, and Rb genes have been reported as well as overexpression of regulators of these pathways, including cyclin-dependent kinase 4 (cdk4) and MDM2.In contrast, alterations in molecules involved in environmental sensing have not been explored in great detail in astrocytomas. Gene expression profiling experiments from our laboratory on a mouse astrocytoma model have implicated the novel cadherin molecule, T-or H-cadherin, in astrocytoma progression. Based on these initial observ...

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Astrocyte-specific expression of CDK4 is not sufficient for tumor formation, but cooperates with p53 heterozygosity to provide a growth advantage for astrocytes in vivo

Cited by 21 publications

References 31 publications

PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion

PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion

The cell cycle and cancer

T-Cadherin-Mediated Cell Growth Regulation Involves G₂ Phase Arrest and Requires p21^CIP1/WAF1 Expression

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Astrocyte-specific expression of CDK4 is not sufficient for tumor formation, but cooperates with p53 heterozygosity to provide a growth advantage for astrocytes in vivo

Cited by 21 publications

References 31 publications

PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion

PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion

The cell cycle and cancer

T-Cadherin-Mediated Cell Growth Regulation Involves G2 Phase Arrest and Requires p21CIP1/WAF1 Expression

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Product

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T-Cadherin-Mediated Cell Growth Regulation Involves G₂ Phase Arrest and Requires p21^CIP1/WAF1 Expression