PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation

Dou, Xiaoyan; Wei, Jing; Sun, Aiqin; Shao, Gang; Childress, Chandra; Yang, Wannian; Lin, Qiong

doi:10.1186/s12935-015-0178-0

Cited by 53 publications

(42 citation statements)

References 37 publications

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“…Depletion of cell cycle regulators can cause radiosensitisation ( Ayllon and O'Connor, 2007 ; Dou et al , 2015 ; Lei et al , 2015 ). In support of this argument, cell cycle regulatory kinases including CDC2, ATM, CDKN2B, CDK5R1 and PLK4 were highly ranked in the screen that identified TOPK ( Tiwana et al , 2015 ).…”

Section: Discussionmentioning

confidence: 99%

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy

et al. 2017

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Background:Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers.Methods:Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy.Results:TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G1/S transition and G2/M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy.Conclusions:This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types.

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Section: Discussionmentioning

confidence: 99%

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy

et al. 2017

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“…Actually, TOPK is upregulated upon activation of insulin-like growth factor 1 (IGF1) signaling [ 34 ]. It is reported to be the target gene of Hippo-YAP signaling [ 35 ] and EWS-FLI1pathway [ 36 ]. Expression of TOPK is regulated by cell cycle-specific transcription factors c-Myc, E2F [ 37 ] and CREB/ATF [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun

Yang

et al. 2016

Oncotarget

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Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have shown promising clinical efficacy in non-squamous non-small cell lung cancer (NSCLC); however, resistance is frequently observed in malignant cells, operating through a mechanism that remains largely unknown. The present study shows that T-lymphokine-activated killer cell-originated protein kinase (TOPK) is upregulated in NSCLC and excessively activated in TKI-refractory cells. TOPK dictates the responsiveness of lung cancers to the EGFR-targeted TKI gefitinib through the transcription factor AP-1 component c-Jun. TOPK binds directly to and phosphorylates c-Jun, which consequently activates the transcription of AP-1 target genes, including CCND1 and CDC2. TOPK silencing sensitizes EGFR-TKI-resistant lung cancer cells to gefitinib and increases gefitinib efficacy in preclinical lung adenocarcinoma xenograft models. These findings represent a novel mechanism of lung cancer resistance to TKIs and suggest that TOPK may have value both as a predictive biomarker and as a therapeutic target: TOPK-targeted therapy may synergize with EGFR-targeted therapy in lung cancers.

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“…A previous study identified PBK as a downstream target of Hippo/YAP signaling [24], so we examined total and phospho-YAP levels in parental and PBK KO U2OS cells to determine if loss of PBK would affect the status of YAP. We found no noticeable changes to the total YAP protein level, nor did we see any changes to phosphorylation levels at S127 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A recent report uncovered that PBK expression is regulated by Yes-associated protein (YAP), a transcriptional co-activator of the Hippo pathway [22,23], and is responsive to geranylgeranyl signaling in ER- breast cancer cells [24]. In this report, we identified additional CDK1/cyclin B phosphorylation sites on PBK and elucidate the role of the CDK1/PBK axis in breast cancer.…”

Section: Introductionmentioning

confidence: 85%

CDK1-mediated mitotic phosphorylation of PBK is involved in cytokinesis and inhibits its oncogenic activity

Stauffer

Zeng

Zhou

et al. 2017

Cellular Signalling

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PDZ-binding kinase (PBK) plays a major role in proliferation and in safeguarding mitotic fidelity in cancer cells. Frequently upregulated in many cancers, PBK drives tumorigenesis and metastasis. PBK has been shown to be phosphorylated in mitosis by cyclin-dependent kinase 1 (CDK1)/cyclin B, however, no studies have been done examining PBK mitotic phosphorylation in oncogenesis. Additionally to the previously identified Threonine-9 phosphorylation, we found that Threonine-24, Serine-32, and Serine-59 of PBK are also phosphorylated. PBK is phosphorylated in vitro and in cells by CDK1 during antimitotic drug-induced mitotic arrest and in normal mitosis. We demonstrated that mitotic phosphorylation of Threonine-9 is involved in cytokinesis. The non-phosphorylatable mutant PBK-T9A augments tumorigenesis to a greater extent than wild type PBK in breast cancer cells, suggesting that PBK mitotic phosphorylation inhibits its tumor promoting activity. The PBK-T9A mutant also transforms and increases the proliferation of immortalized breast epithelial cells. Collectively, this study reveals that CDK1-mediated mitotic phosphorylation of PBK is involved in cytokinesis and inhibits its oncogenic activity.

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PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation

Cited by 53 publications

References 37 publications

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy

TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun

CDK1-mediated mitotic phosphorylation of PBK is involved in cytokinesis and inhibits its oncogenic activity

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