Why minimal is not optimal: Driving the mammalian cell cycle—and drug discovery—with a physiologic CDK control network

Merrick, Karl A.; Fisher, Robert P

doi:10.4161/cc.20758

Cited by 13 publications

(12 citation statements)

References 45 publications

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“…Cdk2 performs exclusive and essential catalytic functions when it is expressed at physiologic levels and when nonphysiologic compensation by other CDKs is thus prevented. 78,99 I propose that a single CAK is necessary and sufficient to activate Cdk1, Cdk2, Cdk4, and Cdk6 in metazoans (Fig. 1).…”

Section: Cdk Activation: a Pathway For Every Occasionmentioning

confidence: 99%

The CDK Network: Linking Cycles of Cell Division and Gene Expression

Fisher

2012

Genes & Cancer

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Cyclin-dependent kinases (CDKs) play essential roles in cell proliferation and gene expression. Although distinct sets of CDKs work in cell division and transcription by RNA polymerase II (Pol II), they share a CDK-activating kinase (CAK), which is itself a CDK-Cdk7-in metazoans. Thus a unitary CDK network controls and may coordinate cycles of cell division and gene expression. Recent work reveals decisive roles for Cdk7 in both pathways. The CAK function of Cdk7 helps determine timing of activation and cyclin-binding preferences of different CDKs during the cell cycle. In the transcription cycle, Cdk7 is both an effector kinase, which phosphorylates Pol II and other proteins and helps establish promoter-proximal pausing; and a CAK for Cdk9 (P-TEFb), which releases Pol II from the pause. By governing the transition from initiation to elongation, Cdk7, Cdk9 and their substrates influence expression of genes important for developmental and cell-cycle decisions, and ensure co-transcriptional maturation of Pol II transcripts. Cdk7 engaged in transcription also appears to be regulated by phosphorylation within its own activation (T) loop. Here I review recent studies of CDK regulation in cell division and gene expression, and propose a model whereby mitogenic signals trigger a cascade of CDK T-loop phosphorylation that drives cells past the restriction (R) point, when continued cell-cycle progression becomes growth factor-independent. Because R-point control is frequently deregulated in cancer, the CAK-CDK pathway is an attractive target for chemical inhibition aimed at impeding the inappropriate commitment to cell division.

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Section: Cdk Activation: a Pathway For Every Occasionmentioning

confidence: 99%

The CDK Network: Linking Cycles of Cell Division and Gene Expression

Fisher

2012

Genes & Cancer

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“…The enzymatic activity of CDKs is regulated by complex mechanisms that include posttranslational modifications and expression of activating and inhibitory proteins (1,2,6,7). The spatial and temporal changes in the activity of these CDK complexes are thought to generate the distinct substrate specificities that lead to sequential and unidirectional progression of the cell cycle (1,8,9).…”

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confidence: 99%

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

Pabla

Gibson

Buege

et al. 2015

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

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Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, using mouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.

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“…Degradation of SLBP at the end of S phase requires specific phosphorylations of two threonines in N-terminal TTP (aa 60-62) motif 8 . The initial trigger for the late S phase degradation of SLBP is Thr 61 phosphorylation by cyclinA/Cdk1 13 , which emerges to be important regulator of S-G2 transition [14][15][16][17] . The phosphorylation of Thr 61 depends on a downstream cyclin binding motif which is critical for the proper recruitment of cyclinA/Cdk1 to SLBP.…”

Section: Introductionmentioning

confidence: 99%

DDB1 and CUL4 associated factor 11 (DCAF11) mediates degradation of Stem-loop binding protein at the end of S phase

2016

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In eukaryotes, bulk histone expression occurs in the S phase of the cell cycle. This highly conserved system is crucial for genomic stability and proper gene expression. In metazoans, Stem-loop binding protein (SLBP), which binds to 3' ends of canonical histone mRNAs, is a key factor in histone biosynthesis. SLBP is mainly expressed in S phase and this is a major mechanism to limit bulk histone production to the S phase. At the end of S phase, SLBP is rapidly degraded by proteasome, depending on two phosphorylations on Thr 60 and Thr 61. Previously, we showed that SLBP fragment (aa 51-108) fused to GST, is sufficient to mimic the late S phase (S/G2) degradation of SLBP. Here, using this fusion protein as bait, we performed pull-down experiments and found that DCAF11, which is a substrate receptor of CRL4 complexes, binds to the phosphorylated SLBP fragment. We further confirmed the interaction of full-length SLBP with DCAF11 and Cul4A by co-immunoprecipitation experiments. We also showed that DCAF11 cannot bind to the Thr61/Ala mutant SLBP, which is not degraded at the end of S phase. Using ectopic expression and siRNA experiments, we demonstrated that SLBP expression is inversely correlated with DCAF11 levels, consistent with the model that DCAF11 mediates SLBP degradation. Finally, we found that ectopic expression of the S/G2 stable mutant SLBP (Thr61/Ala) is significantly more toxic to the cells, in comparison to wild type SLBP. Overall, we concluded that CRL4-DCAF11 mediates the degradation of SLBP at the end of S phase and this degradation is essential for the viability of cells.

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Why minimal is not optimal: Driving the mammalian cell cycle—and drug discovery—with a physiologic CDK control network

Cited by 13 publications

References 45 publications

The CDK Network: Linking Cycles of Cell Division and Gene Expression

The CDK Network: Linking Cycles of Cell Division and Gene Expression

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

DDB1 and CUL4 associated factor 11 (DCAF11) mediates degradation of Stem-loop binding protein at the end of S phase

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