Accumulation of high levels of the p53 and p130 growth-suppressing proteins in cell lines stably over-expressing cyclin-dependent kinase 6 (cdk6)

Nagasawa, Mitsuru; Gelfand, Erwin W.; Lucas, Joseph J.

doi:10.1038/sj.onc.1204396

Cited by 19 publications

(14 citation statements)

References 74 publications

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“…Activation of cyclin E/cdk2 results in phosphorylation of pRb (to the hyperphosphorylated form), completion of G 1 phase, and S phase entry. Consistent with this model are results showing that enforced overexpression of cdk6 in mouse 3T3 fibroblasts or human breast epithelial cells markedly decreased the growth rate of cells, whereas a dominant-negative form of cdk6 had no such effect (70,71).…”

Section: Discussionsupporting

confidence: 68%

Identification of Multiple Cell Cycle Regulatory Functions of p57Kip2 in Human T Lymphocytes

Domenico

Lucas

et al. 2004

The Journal of Immunology

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The specific functions of p57Kip2 in lymphocytes have not yet been fully elucidated. In this study, it is shown that p57Kip2, which is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors, is present in the nuclei of normal resting (G0) T cells from peripheral blood and in the nuclei of the T cell-derived Jurkat cell line. Activation through the TCR results in rapid transport of cytoplasmic cyclin-dependent kinase 6 (cdk6) to nuclei, where it associates with cyclin D and p57Kip2 in active enzyme complexes. Using purified recombinant proteins, it was shown in vitro that addition of p57Kip2 protein to a mixture of cyclin D2 and cdk6 enhanced the association of the latter two proteins and resulted in phosphorylation of p57Kip2. To probe further the function of p57Kip2, Jurkat cells stably transfected with a plasmid encoding p57Kip2 under control of an inducible (tetracycline) promoter were made. Induction of p57Kip2 resulted in increased association of cdk6 with cyclin D3, without receptor-mediated T cell stimulation. The overall amounts of cdk6 and cyclin D3, and also of cdk4 and cyclin E, remained unchanged. Most notably, increased p57Kip2 levels resulted in marked inhibition of both cyclin E- and cyclin A-associated cdk2 kinase activities and a decrease in cyclin A amounts. Therefore, although facilitating activation of cdk6, the ultimate outcome of p57Kip2 induction was a decrease in DNA synthesis and cell proliferation. The results indicate that p57Kip2 is involved in the regulation of several aspects of the T cell cycle.

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Section: Discussionsupporting

confidence: 68%

Identification of Multiple Cell Cycle Regulatory Functions of p57Kip2 in Human T Lymphocytes

Domenico

Lucas

et al. 2004

The Journal of Immunology

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“…In one study, NIH3T3 cells overexpressing cdk6 showed a reduced growth rate compared to parental 3T3 cells, possibly through a mechanism involving the accumulation of p53 and p130 growthsuppressing proteins. 32 A similar effect was seen in breast tumor cell lines. Cell lines transfected with cdk6 showed a reduced rate of proliferation compared with parental tumor cell lines and, interestingly, normal mammary epithelial cells had a high level of cdk6 protein while breast tumor-derived cell lines had much lower levels of cdk6.…”

Section: Cdk6 Blocks Differentiationsupporting

confidence: 62%

From Cell Cycle to Differentiation: An Expanding Role for Cdk6

Grossel¹,

Hinds²

2005

Cell Cycle

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“…Importantly, they showed that restoration of CDK6 in breast cancer cells restrained their proliferation (13). Similarly, NIH3T3 lines engineered to overexpress CDK6 all exhibit reduced rate of proliferation relative to parental control cells (27). It is thus attractive to speculate that enhanced CDK6 expression in parkin-expressing MCF7 cells participates to mitigate the proliferation rate of these cells.…”

Section: Discussionmentioning

confidence: 99%

Parkin Enhances the Expression of Cyclin-dependent Kinase 6 and Negatively Regulates the Proliferation of Breast Cancer Cells*

Tay

Yeo²,

Chai

et al. 2010

Journal of Biological Chemistry

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Although mutations in the parkin gene are frequently associated with familial Parkinsonism, emerging evidence suggests that parkin also plays a role in cancers as a putative tumor suppressor. Supporting this, we show here that parkin expression is dramatically reduced in several breast cancer-derived cell lines as well as in primary breast cancer tissues. Importantly, we found that ectopic parkin expression in parkin-deficient breast cancer cells mitigates their proliferation rate both in vitro and in vivo, as well as reduces the capacity of these cells to migrate. Cell cycle analysis revealed the arrestment of a significant percentage of parkin-expressing breast cancer cells at the G1-phase. However, we did not observe significant changes in the levels of the G1-associated cyclin D1 and E. On the other hand, the level of cyclin-dependent kinase 6 (CDK6) is dramatically and selectively elevated in parkin-expressing breast cancer cells, the extent of which correlates well with the expression of parkin. Interestingly, a recent study demonstrated that CDK6 restrains the proliferation of breast cancer cells. Taken together, our results support a negative role for parkin in tumorigenesis and provide a potential mechanism by which parkin exerts its suppressing effects on breast cancer cell proliferation.Mutations in the parkin gene, located on chromosome 6q25.2-27, are a predominant cause of inherited parkinsonism (1). Accordingly, much of the interest in characterizing the function of the parkin gene has been directed toward understanding its role in neurodegeneration. However, aberrant parkin function has also been linked to several other disorders (2, 3), among which, to the development of several types of cancers (4). Comparatively, the role of parkin in these disorders is less well characterized.Supporting a role for parkin in cancers, a previous study by Cesari et al. (4) involving physical mapping combined with loss of heterozygosity (LOH) 4 analysis identified the 6q-located, 1.4 Mb parkin as a gene that is frequently targeted by hemizygous deletion and inactivation in both malignant tumors and tumorderived cell lines. Following this discovery, several other groups have reported parkin gene alterations and expression variability in a variety of tumor biopsies and tumor cell lines representing a wide range of cancers including breast and ovarian cancers (4 -8). Frequently, diminished or absent parkin expression was observed in these cancers, suggesting that parkin may have tumor suppression properties. Consistent with this, microcellmediated transfer of human chromosome 6 suppresses tumorigenicity in several cancer cell lines (9), and introduction of an intact chromosome 6 into MCF7 (a breast cancer cell line) restores its ability to senesce (10). Collectively, these studies support the existence of a tumor suppressor gene (TSG) on chromosome 6q and the potential candidacy of parkin as a TSG. However, whether and how the loss of parkin function contributes to the development of cancers are currently not well...

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Accumulation of high levels of the p53 and p130 growth-suppressing proteins in cell lines stably over-expressing cyclin-dependent kinase 6 (cdk6)

Cited by 19 publications

References 74 publications

Identification of Multiple Cell Cycle Regulatory Functions of p57Kip2 in Human T Lymphocytes

Identification of Multiple Cell Cycle Regulatory Functions of p57Kip2 in Human T Lymphocytes

From Cell Cycle to Differentiation: An Expanding Role for Cdk6

Parkin Enhances the Expression of Cyclin-dependent Kinase 6 and Negatively Regulates the Proliferation of Breast Cancer Cells*

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