2013
DOI: 10.1038/onc.2013.137
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Signaling through cyclin D-dependent kinases

Abstract: Research over the past quarter century has identified cyclin D-dependent kinases, CDK4 and CDK6, as the major oncogenic drivers among members of the CDK superfamily. CDK4/6 are rendered hyperactive in the majority of human cancers through a multitude of genomic alterations. Sustained activation of these protein kinases provides cancer cells with the power to enter the cell cycle continuously by triggering G1-S-phase transitions and dramatically shortening the duration of the G1 phase. It has also become clear,… Show more

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Cited by 255 publications
(226 citation statements)
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“…The canonical mechanisms of pRb phosphorylation and subsequent functional inactivation have been the subject of several detailed reviews (12)(13)(14) and are not discussed in detail here. As mentioned above, cancer cells need to overcome the pRb-dependent restriction point, and commonly do so through alterations that lead to constitutive cyclin D-CDK4/6 activation, or through loss of pRb itself.…”
Section: Introductionmentioning
confidence: 99%
“…The canonical mechanisms of pRb phosphorylation and subsequent functional inactivation have been the subject of several detailed reviews (12)(13)(14) and are not discussed in detail here. As mentioned above, cancer cells need to overcome the pRb-dependent restriction point, and commonly do so through alterations that lead to constitutive cyclin D-CDK4/6 activation, or through loss of pRb itself.…”
Section: Introductionmentioning
confidence: 99%
“…17 Similarly, phosphorylation of SMAD2 and SMAD3 results in the elimination of the activation function of a SMAD2/3/4 trimer such as the expression of p15 and p21. 18 CDK6, but not CDK4, binds to EYA2 protein to reduce its half-life. EYA2 is important in transcriptional regulation during organogenesis.…”
Section: Introductionmentioning
confidence: 99%
“…CDK4 and CDK6, activated by D-type cyclins induced by mitogens, initiate in G1 phase the phosphorylation of the tumor suppressor pRb. [1][2][3][4] This leads to pRb inactivation and release of the E2F transcription factor activity necessary for DNA synthesis and cell cycle progression. pRb phosphorylation is then maintained independently of D-type cyclins, and hence of mitogens, by a positive feedback loop linking pRb to E2F-dependent transcription of cyclin E, which leads to CDK2 activation and further phosphorylation of pRb.…”
Section: Introductionmentioning
confidence: 99%