Cell-specific responses to loss of cyclin-dependent kinases

Berthet, Cyril; Kaldis, Philipp

doi:10.1038/sj.onc.1210243

Cited by 84 publications

(75 citation statements)

References 76 publications

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“…Interestingly, double knockouts of Cdk2/Cdk4 (14) and Cdk4/Cdk6 (13) but not Cdk2/Cdk6 (13) are embryonic lethal, suggesting genetic interactions. Therefore, Cdk2 and Cdk4 (as well as Cdk4 and Cdk6) display overlapping functions and can substitute for each other (3,15). In the absence of Cdk2 and Cdk4, we have demonstrated an accumulation of hypophosphorylated Retinoblastoma protein (Rb), which represses E2F-mediated transcription leading to decreased expression of E2F-target genes like Cdk1 and others (14).…”

mentioning

confidence: 93%

“…Analysis of human tumor samples revealed that expression of several Cdks and cyclins are often up-regulated (23). However, gene-knockout studies by us and others (2,15,24) have indicated that none of the previously tested Cdks can completely prevent tumorigenesis. Therefore, we determined whether the loss of Cdk1 prevents cellular transformation and tumor development in vivo.…”

Section: Cdk1 Is Essential For Cellular Proliferation and Early Embrymentioning

confidence: 99%

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Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

Diril

Ratnacaram

Padmakumar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

329

324

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Cyclin-dependent kinase 1 (Cdk1) is an archetypical kinase and a central regulator that drives cells through G2 phase and mitosis. Knockouts of Cdk2, Cdk3, Cdk4, or Cdk6 have resulted in viable mice, but the in vivo functions of Cdk1 have not been fully explored in mammals. Here we have generated a conditional-knockout mouse model to study the functions of Cdk1 in vivo. Ablation of Cdk1 leads to arrest of embryonic development around the blastocyst stage. Interestingly, liver-specific deletion of Cdk1 is well tolerated, and liver regeneration after partial hepatectomy is not impaired, indicating that regeneration can be driven by cell growth without cell division. The loss of Cdk1 does not affect S phase progression but results in DNA re-replication because of an increase in Cdk2/cyclin A2 activity. Unlike other Cdks, loss of Cdk1 in the liver confers complete resistance against tumorigenesis induced by activated Ras and silencing of p53.cancer | knockout mice | cell cycle regulation | polyploidy

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mentioning

confidence: 93%

Section: Cdk1 Is Essential For Cellular Proliferation and Early Embrymentioning

confidence: 99%

Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

Diril

Ratnacaram

Padmakumar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

329

324

View full text Add to dashboard Cite

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“…[15][16][17][18] p27 is regulated at both the expression level and subcellular localization. 12 The absence or reduction of p27 expression has been associated with the aggressive behavior of human malignancies, including breast, gastric, prostate, colon, and lung carcinomas. 19 The exact molecular mechanisms responsible for the down-regulation and mislocalization of p27 remain unknown.…”

Section: P27 and Tumor Progressionmentioning

confidence: 99%

“…This CDK-mediated phosphorylation is inhibited by specific proteins called CDK inhibitors, or CDKIs, of which p27 is a family member. 11,12 Most normal epithelial tissues, including breast, prostate, lung, and ovary, express high nuclear levels of the p27 protein. A variable loss of p27 has been observed in all human malignancies examined to date.…”

Section: P27 and Tumor Progressionmentioning

confidence: 99%

A Crosstalk Imbalance Between p27^Kip1 and Its Interacting Molecules Enhances Breast Carcinogenesis

Wang

Chen

et al. 2012

Cancer Biotherapy and Radiopharmaceuticals

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p27Kip1 (p27) is an inhibitor of cyclin/cyclin-dependent kinase complexes, the nuclear loss of which indicates poor prognoses in various solid tumors. In breast cancer cells, the p27 expression level usually decreases during tumor development and progression. In addition, p27 cytoplasmic mislocalization has been reported, but the exact molecular mechanisms remain unclear. Studies have indicated that its phosphorylation status is the key regulator and that several signal transduction pathways are involved in the regulation of both the expression and distribution of p27. To further understand the signals involved, the differences in the profiles of interacting proteins between tumor and normal cells should be elucidated. It is well known that p27 has various interacting partners, such as cyclin, cyclin-depend kinases, CRM1, Jab1, SKP2, and Spy1. Assays used to profile these proteins show differing intracellular p27 expression and localization depending on the cell-cycle phase. We hypothesize that the imbalance of crosstalk between p27 and the other molecules involved in the same signaling pathways plays an indispensable role in breast cancer carcinogenesis.

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“…As an additional assay of apoptosis, we used an anti-PARP antibody (Cell Signaling Tech Inc., Danvers, MA, USA) by western blot in stable transfected cells; again, we found no evidence of PARP protein cleavage (not shown). Instead, quantitative PCR of NCI-H520 cells stably transfected to overexpress BHLHB3 (Figure 3) and using cyclin D1 as a marker of proliferation (Berthet and Kaldis, 2007) revealed a decrease (0.25 ± 0.04-fold, n ¼ 8) of cyclin D1 mRNA expression (measured using Hs00277039_m1 (CCND1) TaqMan Gene Expression Assays; Applied Biosystems, Foster City, CA, USA) in BHLHB3-transfected versus vector-transfected cells, consistent with western blot analysis ( Figure 3) and with a previous study (Azmi et al, 2004) showing that BHLHB3 overexpression in mouse myoblast cell line C2C12 promotes cell cycle exit in association with decreased levels of cyclin D1 protein expression. Indeed, inhibition of cyclin D1 protein expression is associated with cell cycle arrest in cancer cell lines (Berthet and Kaldis, 2007).…”

mentioning

confidence: 99%

BHLHB3: a candidate tumor suppressor in lung cancer

et al. 2008

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BHLHB3 is a basic helix-loop-helix (bHLH) domaincontaining protein that acts as a transcriptional repressor. We found that BHLHB3 transcript levels were low in three human lung cancer cell lines and downregulated in human lung adenocarcinomas as compared to normal lung tissue. BHLHB3 gene overexpression inhibited colony formation of A549, NCI-H520 and NCI-H596 lung cancer cells. The reduced colony growth was likely due to inhibition of cell proliferation as suggested by the downregulation of cyclin D1 (CCND1) expression in NCI-H520 cells transfected to overexpress the BHLHB3 gene; no evidence of apoptosis was observed. These results point to the potential role of the BHLHB3 protein as a tumor suppressor for lung cancer.

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Cell-specific responses to loss of cyclin-dependent kinases

Cited by 84 publications

References 76 publications

Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

A Crosstalk Imbalance Between p27^Kip1 and Its Interacting Molecules Enhances Breast Carcinogenesis

BHLHB3: a candidate tumor suppressor in lung cancer

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Cell-specific responses to loss of cyclin-dependent kinases

Cited by 84 publications

References 76 publications

Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

A Crosstalk Imbalance Between p27Kip1 and Its Interacting Molecules Enhances Breast Carcinogenesis

BHLHB3: a candidate tumor suppressor in lung cancer

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A Crosstalk Imbalance Between p27^Kip1 and Its Interacting Molecules Enhances Breast Carcinogenesis