Cell Cycle Progression without Cyclin D-CDK4 and Cyclin D-CDK6 Complexes

Kozar, Katarzyna; Siciński, Piotr

doi:10.4161/cc.4.3.1551

Cited by 117 publications

(117 citation statements)

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“…Mice lacking the individual D cyclins and Cdk4 and 6 have been generated with tissue-specific differences between mice. 33 More recently, mice lacking all D cyclins have also been generated, 34 which showed specific defects in the hematopoietic system and died at embryonal day 17.5. Mice lacking Cdk4/6 had a very comparable phenotype, and died early during embryonal development with multi-lineage hematopoietic abnormalities.…”

Section: P276-00 Is Active In An MM Xenograft Modelmentioning

confidence: 99%

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

et al. 2009

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Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in 450% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclindependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspasedependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.

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Section: P276-00 Is Active In An MM Xenograft Modelmentioning

confidence: 99%

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

et al. 2009

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“…However, there is functional redundancy among these D-type cyclins, which share a high degree of amino-acid homology with 50-60% identity throughout the coding region. Indeed, mice deficient for individual D-type cyclins show only limited tissuespecific abnormalities (Kozar and Sicinski, 2005). Furthermore, cyclin D2 could substitute the function of cyclin D1 in mouse development (Carthon et al, 2005).…”

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confidence: 99%

Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

et al. 2007

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Cyclin D2 plays an important role in regulation of hematopoietic cell proliferation by cytokines and is implicated in oncogenesis of various hematopoietic malignancies. However, mechanisms regulating cyclin D2 stability and its expression level have remained to be known. Here, we demonstrate that interleukin-3 signaling stabilizes cyclin D2 by inhibition of glycogen synthase kinase-3b (GSK3b) through Janus kinase2-dependent activation of phosphatidylinositol 3 0 -kinase (PI3K)/Akt signaling pathway in hematopoietic 32Dcl3 cells. On the other hand, osmotic stress was shown to induce a rapid proteasomal degradation of cyclin D2, which was mediated by activation of p38. GSK3b and p38 was demonstrated to phosphorylate cyclin D2 on Thr280 in vitro, while a cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells. Inhibition of the PI3K pathway or induction of osmotic stress also caused a rapid proteasomal degradation of cyclin D2 in primary leukemic or myeloma cells. These results indicate that cyclin D2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by Thr280 phosphorylation by GSK3b or p38, which is induced by inhibition of the PI3K pathway or by osmotic stress, respectively.

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“…CDK6 has also been found to be essential for b cell proliferation in pancreas. [12][13][14] However, CDK6 overexpression has also been shown to reduce skin tumorigenesis and cell growth in fibroblasts. 15,16 Phosphorylation of transcription factors CDK4/6 cyclin D complexes phosphorylate transcription factors, such as forkhead box M1 (FOXM1), mothers against decapentaplegic homolog 2/3 (SMAD2/3), eyes absent homolog 2 (EYA2) and methylosome protein 50 (MEP50) (cofactor) to alter their functions.…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8][9][10][11] Nevertheless, this sequential phosphorylation model has been challenged as Kozar et al demonstrated that CDK2-cyclin E complex is capable of phosphorylating Rb in the absence of D-type cyclins to induce E2F transcription factors. 12 Interestingly, genetic analysis has also revealed that many cell types can proliferate in the absence of CDK4/6 or D cyclins. Yet, these studies have also pinpointed specific CDK requirements by specialized type of cells.…”

Section: Introductionmentioning

confidence: 99%

“…[51][52][53][54][55][56][57][58] These observations, coupled with the fact that mice lacking D-type cyclins and/or CDK4/6 are viable, make targeting components of the CDK4/6 cyclin D-INK4-pRb-E2F pathway a highly attractive anti-cancer strategy. 12,14 CDK6 and hematological malignancies Acute myeloid leukemia (AML) is a malignant transformation of hematopoietic cells characterized by an increase in the number of myeloid cells in the marrow and an arrest in their maturation. Chromosomal translocations of band q23 of chromosome 11 of the mixed lineage leukemia (MLL) gene are common in AML and are associated with poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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Cell Cycle Progression without Cyclin D-CDK4 and Cyclin D-CDK6 Complexes

Cited by 117 publications

References 50 publications

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

Targeting CDK6 in cancer: State of the art and new insights

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