Targeted Inactivation of p12Cdk2ap1, CDK2 Associating Protein 1, Leads to Early Embryonic Lethality

Kim, Yong; McBride, Jim; Kimlin, Lauren; Pae, Eung‐Kwon; Deshpande, Amit; Wong, David T.

doi:10.1371/journal.pone.0004518

Cited by 21 publications

(15 citation statements)

References 42 publications

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“…Although this study lacked the population characterization of the previous study (which ruled out contaminant differentiating cells from analysis), its results are consistent with a study showing that the CDK2 inhibitor CDK2-associating protein 1 was required for promoter methylation and down-regulation of Oct4 during differentiation [26]. As this result was obtained in mESCs, this supports a role for CDK2 in controlling pluripotency in mESCs as well as hESCs [27]. …”

Section: The Cell Cycle and The Regulation Of Pluripotencysupporting

confidence: 86%

The cell cycle and pluripotency

Hindley

Philpott

2013

Biochemical Journal

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PSCs (pluripotent stem cells) possess two key properties that have made them the focus of global research efforts in regenerative medicine: they have unlimited expansion potential under conditions which favour their preservation as PSCs and they have the ability to generate all somatic cell types upon differentiation (pluripotency). Conditions have been defined in vitro in which pluripotency is maintained, or else differentiation is favoured and is directed towards specific somatic cell types. However, an unanswered question is whether or not the core cell cycle machinery directly regulates the pluripotency and differentiation properties of PSCs. If so, then manipulation of the cell cycle may represent an additional tool by which in vitro maintenance or differentiation of PSCs may be controlled in regenerative medicine. The present review aims to summarize our current understanding of links between the core cell cycle machinery and the maintenance of pluripotency in ESCs (embryonic stem cells) and iPSCs (induced PSCs).

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Section: The Cell Cycle and The Regulation Of Pluripotencysupporting

confidence: 86%

The cell cycle and pluripotency

Hindley

Philpott

2013

Biochemical Journal

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“…In addition, accumulated evidence has indicated that the expression levels of CDK2AP1 may be used as an indicator in diagnostics for the invasiveness and prognosis of oral squamous cell carcinoma, esophageal squamous cell carcinomas and gastric cancer tissues in humans (10,14). Moreover, a recent study revealed that targeted disruption of murine Cdk2ap1 resulted in embryonic lethality with a high penetration rate, which highlights the essential role of CDK2AP1 in the mammal (22).…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase 2-associated protein 1 suppresses growth and tumorigenesis of lung cancer

Sun

Jiang

Wang

et al. 2013

International Journal of Oncology

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Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1), a growth suppressor that negatively regulates CDK2 activity, has been implicated in various types of cancer; yet its role in lung cancer remains unclear. In the present study, a lentivirus-based system was used to specifically downregulate or upregulate CDK2AP1 expression. A549 lung cancer cells were treated with RNAi (RNA interference) or lentiviral vectors for overexpression. Ectopic overexpression of CDK2AP1 in A549 cells in vitro greatly impaired their proliferation and colony-forming ability and enhanced their chemosensitivity to cisplatin and paclitaxel and caused cell cycle arrest at G1/S transition accompanied by the reduction of expression of CDK4 and CDK7. Injection of the ectopically CDK2AP1-overexpressing A549 cells into nude mice resulted in growth arrest of solid lung cancer tumors in vivo. Knockdown of CDK2AP1 in A549 cells, however, gave rise to the opposite effects including promoting cell proliferation/growth, cell cycling in vitro and enhancing tumorigenesis in vivo. These results suggest that CDK2AP1 plays an important role in modulating the growth and tumorigenesis of lung cancer cells and also has significant effects on the chemosensitivity of pulmonary malignancies to chemotherapeutics. Hence, this study extends our knowledge on the relationship between CDK2AP1 and oncogenesis of lung cancer, indicating that CDK2AP1 may serve as a new molecular target for future lung cancer therapy.

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“…Twist 2 knockout mice have severe growth retardation with atrophic dermis, thymus, liver and fat tissues (22). p12 knockout mice died during gestation but two survived mice have been shown to exhibit craniofacial defects with a short snout and a round forehead compared to wild type animals (23). These results indicate that p12 and Twist 2 are linked to EMT and to the maintenance of mesenchymal lineage during embryogenesis.…”

Section: Emt Of Hcpc-1 Cells Induced By P12cdk2-ap1mentioning

confidence: 99%

Epithelial-Mesenchymal Transition and Cell Cooperativity in Metastasis

2009

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The role of epithelial-mesenchymal transition (EMT) in metastasis remains controversial. EMT has been postulated as an absolute requirement for tumor invasion and metastasis. Three different models including incomplete EMT, mesenchymal-epithelial transition (MET), and collective migration have been proposed for the role of EMT in cancer invasion and metastasis. However, skepticism remains about whether EMT truly occurs during cancer progression, and if it does, whether it plays an indispensible role in metastasis. Our recent findings suggest that EMT cells are responsible for degrading the surrounding matrix to enable invasion and intravasation of both EMT and non-EMT cells. Only non-EMT cells that have entered the blood stream are able to reestablish colonies in the secondary sites. Here, we discuss an alternative model for the role of EMT in cancer metastasis in which EMT and non-EMT cells cooperate to complete the entire process of spontaneous metastasis. [Cancer Res 2009;69(18):7135-9] Epithelial-Mesenchymal Transition and Cancer MetastasisEpithelial-mesenchymal transition (EMT) was first recognized as a central differentiation process in early embryogenic morphogenesis (1). It is a coordinated molecular and cellular change defined as a reduction in cell-cell adhesion, apical-basolateral polarity, and epithelial markers, as well as an acquisition of motility, spindle-cell shape, and mesenchymal markers. The definition of EMT in embryo development, which includes an ordered series of transcriptional events and a switch in cell fate, has not been strictly followed in cancer research, in which this term has been more liberally referred to as a recognizable change in cellular phenotype characterized as loss of cell junctions and gain of migratory behaviors (2).This more inclusive EMT process has been proposed and supported by numerous publications to be a potent mechanism that enhances the detachment of cancer cells from primary tumors. However, it is still controversial whether transformation of a noninvasive tumor into a metastatic tumor truly represents an EMT, and if it is, how important it is in the process of cancer metastasis (3, 4). The main argument for the lack of a role of EMT in cancer is that metastases seem histopathologically similar to the primary tumors from which they are derived. To resolve this apparent contradiction, a mesenchymal-epithelial transition (MET) process in the metastatic sites has been postulated as part of the process of metastatic tumor formation (5). MET is an attractive hypothesis that can explain the histopathological similarity between primary and metastatic tumors. In support of the MET hypothesis, dynamic expression of E-cadherin (CDH1) in cancer progression has been documented. However, direct experimental data supporting MET in cancer metastasis are still lacking. For example, Graff and colleagues showed that the DNA methylation status of the CDH1 promoter varies at different stages of the metastatic process (6). In primary breast cancers, the tumor cells ...

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Targeted Inactivation of p12Cdk2ap1, CDK2 Associating Protein 1, Leads to Early Embryonic Lethality

Cited by 21 publications

References 42 publications

The cell cycle and pluripotency

The cell cycle and pluripotency

Cyclin-dependent kinase 2-associated protein 1 suppresses growth and tumorigenesis of lung cancer

Epithelial-Mesenchymal Transition and Cell Cooperativity in Metastasis

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