The tumor suppressor CDKN3 controls mitosis

Nalepa, Grzegorz; Barnholtz‐Sloan, Jill S.; Enzor, Rikki; Dey, Dilip; He, Yingying; Gehlhausen, Jeff R.; Lehmann, Amalia S.; Park, Su-Jung; Yang, Yanzhu; Yang, Xianlin; Chen, Shi; Guan, Xiaowei; Chen, Yanwen; Renbarger, Jamie L.; Yang, Feng-Chun; Parada, Luis F.; Clapp, Wade

doi:10.1083/jcb.201205125

Cited by 83 publications

(81 citation statements)

References 96 publications

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“…A recent study indicates that KAP dephosphorylates and inactivates Cdc2 during mitotic exit. 33 This effect occurs in addition to the downregulation of Cdc2 expression that we reported previously. 3 Interestingly, ROCK2 regulates cytokinesis 34 and centrosome number.…”

Section: Discussionmentioning

confidence: 59%

KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway

Jiang

et al. 2014

Oncogene

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Aberrant splicing of the cyclin-dependent kinase-associated phosphatase, KAP, promotes glioblastoma invasion in a Cdc2-dependent manner. However, the mechanism by which this occurs is unknown. Here we show that miR-26a, which is often amplified in glioblastoma, promotes invasion in phosphatase and tensin homolog (PTEN)-competent and PTEN-deficient glioblastoma cells by directly downregulating KAP expression. Mechanistically, we find that KAP binds and activates ROCK2. Thus, RNA-mediated downregulation of KAP leads to decreased ROCK2 activity and this, in turn, increases Rac1-mediated invasion. In addition, the decrease in KAP expression activates the cyclin-dependent kinase, Cdk2, and this directly promotes invasion by increasing retinoblastoma phosphorylation, E2F-dependent Cdc2 expression and Cdc2-mediated inactivation of the actomyosin inhibitor, caldesmon. Importantly, glioblastoma cell invasion mediated by this pathway can be antagonized by Cdk2/Cdc2 inhibitors in vitro and in vivo. Thus, two distinct RNA-based mechanisms activate this novel KAP/ROCK2/Cdk2-dependent invasion pathway in glioblastoma.

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Section: Discussionmentioning

confidence: 59%

KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway

Jiang

et al. 2014

Oncogene

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“…To examine the status of the SAC upon FA knockdown, we performed a functional RNAi screen as described previously (25,26). HeLa cells were transfected with arrayed library siRNAs, challenged with taxol to activate the SAC through disruption of spindle microtubules, fixed, and imaged ( Figure 1A).…”

Section: Functional Rnai Screen Reveals Role For Fa Signaling In the mentioning

confidence: 99%

Fanconi anemia signaling network regulates the spindle assembly checkpoint

Nalepa¹,

Enzor²,

Sun³

et al. 2013

J. Clin. Invest.

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Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle-dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway.

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“…In the previous report of the association of CDKN3 with cervical cancer, CDKN3 was shown to behave as an oncogene (Espinosa et al 2013). However, it has been proposed that CDKN3 is a tumor suppressor of mitosis control (Nalepa et al 2013).…”

Section: Mitosis Is the Main Phase Of The Cell Cycle Altered In Cervimentioning

confidence: 99%

Mitosis Targets as Biomarkers in Cervical Cancer

Berúmen¹,

Espinosa²,

Medina³

et al. 2014

Biomarkers in Cancer

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The effectiveness of a preventive human papillomavirus (HPV) vaccination for reducing the cervical cancer (CC) burden will likely not be known for 30 years. Current screening methods for detecting highgrade cervical intraepithelial neoplasias (CIN2/3) and CC (CIN2+) have low sensitivity (Pap test) or low specificity (HPV tests). Improved procedures for CC screening and treatment are therefore required. Based on comparisons with healthy cervical epithelium, the genes most upregulated and enriched in CC are those involved in mitosis. Some of these upregulated genes might be good candidates for CC screening or survival markers or as potential therapeutic targets. In this chapter, we analyze the benefits and limitations of current methods used for early CC detection, the evidence that demonstrates that the most enriched genes in CC are those involved in mitosis, the mechanism that regulates mitosis and its relationship with HPV, and our experimental evidence suggesting that some mitosis genes might be good markers for screening and survival in CC. In addition, we discuss the need to develop less expensive and more efficient methods that can be automated for large-scale application in poor and developing countries. We also discuss the potential use of the markers for other types of cancers and as potential therapeutic targets.

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The tumor suppressor CDKN3 controls mitosis

Abstract: A genome-wide screen of phosphatases that control mitosis identified CDKN3, which acts through the CDC2 signaling axis.

Cited by 83 publications

References 96 publications

KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway

KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway

Fanconi anemia signaling network regulates the spindle assembly checkpoint

Mitosis Targets as Biomarkers in Cervical Cancer

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