Autocatalytic Phosphorylation of CDK2 at the Activating Thr160

Abbas, Tarek; Jha, Sudhakar; Sherman, Nicholas E.; Dutta, Anindya

doi:10.4161/cc.6.7.4000

Cited by 34 publications

(30 citation statements)

References 41 publications

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“…39 Indeed, phosphorylation of threonine-160, a mark of CDK2 activation that is inhibited on association with P21, was increased in p21 knockdown/Cre;Scl fl/fl MkPs by 1.5-to 2-fold ( Figure 7F). …”

Section: P21 Levels Are Critical In Megakaryopoiesismentioning

confidence: 95%

SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis

Chagraoui

Kassouf

Banerjee

et al. 2011

Blood

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Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in lossof-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genomewide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Sclmutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation. (Blood. 2011;118(3):723-735) IntroductionMegakaryocytes (MKs) are specialized blood cells that release platelets, the effectors of coagulation processes. During megakaryopoiesis, megakaryocyte progenitors (MkPs) coordinately proliferate and differentiate to develop into mature MKs that, ultimately, shed platelets. This complex biologic process requires profound cellular and nuclear changes (cytoplasm remodeling, cell size increase, nuclear polyploidization, and cytoskeletal dynamics) relying on an exquisite coordination of key cellular and molecular mechanisms. 1 At an early stage in their development, MKs enter endomitosis (or abortive mitosis), during which DNA replicates without cell division. This process results in nuclear polyploidization, increase in cell size, and is linked to platelet formation. 2,3 Formation of the demarcation membrane system (DMS, a reservoir for proplatelet membranes) and secretory granules reflects some of the specific characteristics of the cytoplasmic maturation of MKs. 4,5 Signaling by thrombopoietin (TPO), the major megakaryocytic cytokine, induces PI3K activity, downstream of which lies the mammalian target of rapamycin pathway. 6 Mammalian target of rapamycin is a kinase that controls cell size and cell-cycle progression in mammals and Drosophila. 7,8 It also regulates key MK attributes (proliferation, cell size, cytoskeleton organization, and platelet formation) in part through control of G 1 /S cell-cycle progression. 6,9 This control is mediated by sequential action of the cell-cycle regulators cyclin D3 (CCND3) and P21 (cyclindependent cell-cycle inhibitor, CDKN1a). 9 In mouse MKs, cyclin D3 expression is hig...

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Section: P21 Levels Are Critical In Megakaryopoiesismentioning

confidence: 95%

SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis

Chagraoui

Kassouf

Banerjee

et al. 2011

Blood

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“…Two reports have suggested that specific CDKs are capable of bypassing the CAK requirement through autoactivation. Cdk2 was apparently phosphorylated when expressed as a monomer in bacteria under certain conditions, 63 which could not be reproduced in eukaryotic cells or in vitro. Cdk9 was also posited to phosphorylate its own T loop, 64 but direct tests of autocatalytic activation starting with unphosphorylated Cdk9 did not support this idea.…”

Section: The Cak We Knowmentioning

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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“…Cdc6 might have an additional independent function to control Thr-160 T-loop phosphorylation of Cdk2, but so far we have no data to support this scenario. Alternatively, the elevated T-loop phosphorylation might be a mere consequence of autocatalytic Thr-160 phosphorylation of the Cdk2 that is activated by Cdc6-mediated removal of the bound p27 as reported (27).…”

Section: Discussionmentioning

confidence: 99%