Beyond the cell cycle: A new role for Cdk6 in differentiation

Grossel, Martha J.; Hinds, Philip W.

doi:10.1002/jcb.20712

Cited by 77 publications

(68 citation statements)

References 48 publications

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“…The CDK6 gene is frequently amplified or overexpressed in a variety of human cancers (Grossel and Hinds, 2006a), such as glioblastoma (Wiedemeyer et al, 2010), myxofibrosarcoma (Tsai et al, 2012), and lymphoid malignancies (Nagel et al, 2008). By accelerating progression through G1/S phase checkpoint of the cell cycle, overexpression of CDK6 increased cell proliferation and reduced DNA repair capacity.…”

Section: Discussionmentioning

confidence: 99%

Retracted: Let-7a Functions as a Tumor Suppressor in Ewing's Sarcoma Cell Lines Partly by Targeting Cyclin-Dependent Kinase 6

Zhang

Yu²,

Chen³

et al. 2014

DNA and Cell Biology

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MicroRNAs play an important role in the development and progression of Ewing's sarcoma (ES). Especially, the expression of let-7a has been reported to be significantly downregulated in various cancers, and can affect the initiation and maintenance of tumor progression. However, the relative effects of let-7a on ES cells and relative mechanisms are largely unknown. In this study, we identified the underexpression of let-7a in human ES cells comparing with the human mesenchymal stem cells. Then, we sought to compensate for its loss through exogenous transfection with let-7a mimic into ES cell lines A673 and SK-ES-1. Restored let-7a expression inhibited cell proliferation, migration, as well as invasion; arrested cell cycle progression; and induced cell apoptosis of both cell lines. Moreover, bioinformatic prediction suggested that cyclin-dependent kinase 6 (CDK6), which is overexpressed and functions as an oncoprotein in ES cells, is a putative target gene of let-7a. Using mRNA and protein expression analysis and luciferase assays, we further identified the target role of CDK6. Finally, we found that restored CDK6 expression in ES cells that had been treated with let-7a mimic before could partly dampen let-7a-mediated tumor suppression. Taken together, our results showed that let-7a acted as a tumor suppressor in ES by targeting CDK6, and it may provide novel diagnostic and therapeutic options for human Ewing sarcoma clinical operation in future.

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Section: Discussionmentioning

confidence: 99%

Retracted: Let-7a Functions as a Tumor Suppressor in Ewing's Sarcoma Cell Lines Partly by Targeting Cyclin-Dependent Kinase 6

Zhang

Yu²,

Chen³

et al. 2014

DNA and Cell Biology

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“…Of interest, one major discrepancy between Cdk4 and Cdk6 is the specific role of the latter in blocking differentiation of multiple lineages [69]. For instance, although Cdk4 and Cdk6 are expressed all along the hematopoietic lineage, Cdk6 deficiency specifically impaired expansion of lineage-committed populations rather than proliferation of early hematopoietic precursors [10], a situation mimicking the phenotype we observed in the brain.…”

Section: Discussionmentioning

confidence: 52%

“…Importantly, while the long held belief was that all Cdks were expressed in most proliferating cell types [43,69], we were able to detect Cdk1, Cdk4, and Cdk6 but not Cdk2 expression in the DG and SVZ (our unpublished observations), although a recent article reported a critical role Data are presented as mean 6 SD. Statistical analysis were two-way ANOVA followed by a Bonferroni's post-test.…”

Section: Discussionmentioning

confidence: 70%

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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“…In addition to pRb, Cdk6 substrates include pRb2/p130, histone H1, and Bcl-2 (25)(26)(27). The appropriate regulation of Cdk6 activity determines differentiation of many cell types and a variety of tumors have been associated with elevated levels of Cdk6 expression (28)(29)(30)(31)(32)(33). Careful inspection of human Cdk6 revealed a peculiar gene structure with particularly long introns and a predicted 3Ј untranslated region (UTR) spanning nearly 11 Kb (Fig.…”

Section: Tdp-43 Inhibits Cdk6mentioning

confidence: 99%

TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression

Ayala

Misteli

Baralle

2008

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

214

197

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T DP-43 belongs to the family of heterogeneous nuclear ribonucleoproteins (hnRNPs) and binds single-stranded RNA via its N-terminal RNA recognition motif (1). Members of the hnRNP family serve multiple roles in the generation and processing of RNA, including transcription, splicing, transport, and stability. TDP-43 inhibits exon recognition during splicing upon recruitment to the 3Ј splice site of the cystic fibrosis transmembrane conductance regulator (CFTR) and apolipoprotein AII transcripts via a sequence of GU repeats (2-5). The binding affinity of the recombinant human, worm, and fly homologues for this target sequence is remarkably high, measured in the low nanomolar range (6). TDP-43 also has been implicated in the transcription regulation of HIV and the spermatid-specific gene SP-10 through promoter association (7,8). More recently, TDP-43 was identified as the main ubiquitinated component of cytoplasmic inclusions in neurodegenerative diseases, specifically frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) (9, 10). Abnormal aggregation of TDP-43 in the cytoplasm now is thought to define a class of frontotemporal dementias termed TDP-43 proteinopathies. Mislocalization and the consequent loss of TDP-43 function in neuronal cells may represent a common event in FTLD pathogenesis. Despite the increasing awareness of processes involving TDP-43, the cellular role of the protein still is poorly defined.We depleted TDP-43 by RNA interference (RNAi) to identify TDP-43-regulated transcripts. Our results point to cyclindependent kinase 6 (Cdk6) as a unique target of TDP-43 regulation and suggest that TDP-43 inhibits Cdk6 expression through recruitment to the GU-rich transcript. Simultaneously, we found that TDP-43 silencing alters cell cycle distribution and induces apoptosis. Table 1 lists 16 of these proteins whose functions have been associated with retinoblastoma protein (pRb) activity. The tumor suppressor pRb is essential for the control of cell cycle progression, cellular differentiation, and maintenance of genome integrity. Inactivation of pRb occurs through its gradual phosphorylation by Cdks during the G 1 phase of the cell division cycle resulting in the activation of transcription factors that promote cell proliferation and enable transition on to the S phase (see ref. 11 for review). Our RNA microarray analyses showed altered levels of transcripts coding for proteins whose functions are related to the control of cell cycle progression (Cdk6, POLD4, cyclin B1, Cdk2, UBE2C, and SKP2). In addition, some of these factors are known to either directly interact with pRb (e.g., HDAC1, RBBP4, and CRI1), or act in response to pRb modulation (e.g., E2F8 and NAP1L1) (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).

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Beyond the cell cycle: A new role for Cdk6 in differentiation

Cited by 77 publications

References 48 publications

Retracted: Let-7a Functions as a Tumor Suppressor in Ewing's Sarcoma Cell Lines Partly by Targeting Cyclin-Dependent Kinase 6

Retracted: Let-7a Functions as a Tumor Suppressor in Ewing's Sarcoma Cell Lines Partly by Targeting Cyclin-Dependent Kinase 6

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression

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