Mice thrive without Cdk4 and Cdk2

Barrière, Cédric; Santamarı́a, David; Cerqueira, Antonio; Galán, Javier; Martín, Alberto; Ortega, Sagrario; Malumbres, Marcos; Dubus, Pierre; Barbacid, Mariano

doi:10.1016/j.molonc.2007.03.001

Cited by 106 publications

(87 citation statements)

References 23 publications

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“…Our results are in accordance with other studies that have previously shown that Cdk4 deficiency does not impede cell proliferation in several highly proliferating tissues, such as skin, small intestine, or hematopoietic system [63,64]. In addition, Cdk4 is dispensable for liver regeneration following partial hepatectomy [64], an assay considered to be one of the most stringent to evaluate the proliferative capacity of an adult tissue [65]. Altogether, these data support that Cdk4 is, with the exception of certain cell types [9,19,66,67], overall dispensable for adult tissue homeostasis.…”

Section: Discussionsupporting

confidence: 93%

“…This work shows that although Cdk4 is expressed in SGZ and SVZ precursors, this kinase is dispensable for cell proliferation in adult neurogenic niches, at least in our experimental conditions. Our results are in accordance with other studies that have previously shown that Cdk4 deficiency does not impede cell proliferation in several highly proliferating tissues, such as skin, small intestine, or hematopoietic system [63,64]. In addition, Cdk4 is dispensable for liver regeneration following partial hepatectomy [64], an assay considered to be one of the most stringent to evaluate the proliferative capacity of an adult tissue [65].…”

Section: Discussionsupporting

confidence: 92%

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Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

et al. 2011

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The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G 1 regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G 1 phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G 1 length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. STEM CELLS 2011;29:713-724 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

et al. 2011

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“…We generated a tamoxifen-inducible model for FAK deletion in adult mice, RERTn ERT/ERT Cre;FAK fl/fl and confirm efficient FAK deletion at the protein level in this system (Supplementary Figs 1A-D, 2A, B) [30][31][32] . RERTn ERT/ERT Cre mice have been used previously to induce global deletion of target genes 31 .…”

Section: Fak Deletion Increases Metastases In the Rip-tag2 Modelmentioning

confidence: 73%

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

et al. 2014

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Metastasis is the main cause of cancer-related death and thus understanding the molecular and cellular mechanisms underlying this process is critical. Here, our data demonstrate, contrary to established dogma, that loss of haematopoietic-derived focal adhesion kinase (FAK) is sufficient to enhance tumour metastasis. Using both experimental and spontaneous metastasis models, we show that genetic ablation of haematopoietic FAK does not affect primary tumour growth but enhances the incidence of metastasis significantly. At a molecular level, haematopoietic FAK deletion results in an increase in PU-1 levels and decrease in GATA-1 levels causing a shift of hematopoietic homeostasis towards a myeloid commitment. The subsequent increase in circulating granulocyte number, with an increase in serum CXCL12 and granulocyte CXCR4 levels, was required for augmented metastasis in mice lacking haematopoietic FAK. Overall our findings provide a mechanism by which haematopoietic FAK controls cancer metastasis.

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“…Genetic ablation of CDK2 has little effect on cellular proliferation during early murine development (16)(17)(18). Furthermore, depletion of CDK2 using siRNAs or antisense oligonucleotides has little effect on the proliferation rates of various colon cancer lines (19).…”

mentioning

confidence: 99%

Chemical-genetic analysis of cyclin dependent kinase 2 function reveals an important role in cellular transformation by multiple oncogenic pathways

Horiuchi¹,

Huskey²,

Kusdra³

et al. 2012

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

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A family of conserved serine/threonine kinases known as cyclindependent kinases (CDKs) drives orderly cell cycle progression in mammalian cells. Prior studies have suggested that CDK2 regulates S-phase entry and progression, and frequently shows increased activity in a wide spectrum of human tumors. Genetic KO/ knockdown approaches, however, have suggested that lack of CDK2 protein does not prevent cellular proliferation, both during somatic development in mice as well as in human cancer cell lines. Here, we use an alternative, chemical-genetic approach to achieve specific inhibition of CDK2 kinase activity in cells. We directly compare small-molecule inhibition of CDK2 kinase activity with siRNA knockdown and show that small-molecule inhibition results in marked defects in proliferation of nontransformed cells, whereas siRNA knockdown does not, highlighting the differences between these two approaches. In addition, CDK2 inhibition drastically diminishes anchorage-independent growth of human cancer cells and cells transformed with various oncogenes. Our results establish that CDK2 activity is necessary for normal mammalian cell cycle progression and suggest that it might be a useful therapeutic target for treating cancer.analog-sensitive kinase | cyclin-dependent kinase

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Mice thrive without Cdk4 and Cdk2

Cited by 106 publications

References 23 publications

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

Chemical-genetic analysis of cyclin dependent kinase 2 function reveals an important role in cellular transformation by multiple oncogenic pathways

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