Distinct proliferative and transcriptional effects of the D-type cyclins in vivo

Mullany, Lisa K.; White, Peter; Hanse, Eric A.; Nelsen, Christopher J.; Goggin, Melissa; Mullany, Joseph E.; Anttila, Chelsea K.; Greenbaum, Linda E.; Kaestner, Klaus H.; Albrecht, Jeffrey H.

doi:10.4161/cc.7.14.6274

Cited by 76 publications

(73 citation statements)

References 44 publications

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“…This model is supported by evidence that an siRNA-mediated reduction in cyclin D1 expression during estrogen stimulation leads to a proportional decrease in induction of cyclin E2 and that induction of cyclin D1 is sufficient for increased cyclin E2 expression and E2F1 recruitment to the cyclin E2 gene promoter. Recent evidence that cyclin E2 expression is increased when cyclin D1, D2, or D3 is transiently expressed in hepatocytes provides further support (44).…”

Section: Discussionmentioning

confidence: 81%

Estrogen Regulation of Cyclin E2 Requires Cyclin D1 but Not c-Myc

Caldon

Sergio

Schütte

et al. 2009

Molecular and Cellular Biology

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During estrogen-induced proliferation, c-Myc and cyclin D1 initiate independent pathways that activate cyclin E1-Cdk2 by sequestration and/or downregulation of the CDK inhibitor p21Waf1/Cip1 , without significant increases in cyclin E1 protein levels. In contrast, cyclin E2 undergoes a marked increase in expression, which occurs within 9 to 12 h of estrogen treatment of antiestrogen-pretreated MCF-7 breast cancer cells. Both E cyclins are important to estrogen action, as small interfering RNA (siRNA)-mediated knockdown of either cyclin E1 or cyclin E2 attenuated estrogen-mediated proliferation. Inducible expression of cyclin D1 upregulated cyclin E2, while siRNA-mediated knockdown of cyclin D1 attenuated estrogen effects on cyclin E2. However, manipulation of c-Myc levels did not profoundly affect cyclin E2. Cyclin E2 induction by estrogen was accompanied by recruitment of E2F1 to the cyclin E1 and E2 promoters, and cyclin D1 induction was sufficient for E2F1 recruitment. siRNA-mediated knockdown of the chromatin remodelling factor CHD8 prevented cyclin E2 upregulation. Together, these data indicate that cyclin E2-Cdk2 activation by estrogen occurs via E2F-and CHD8-mediated transcription of cyclin E2 downstream of cyclin D1. This contrasts with the predominant regulation of cyclin E1-Cdk2 activity via CDK inhibitor association downstream of both c-Myc and cyclin D1 and indicates that cyclins E1 and E2 are not always coordinately regulated.In mammalian cells, there are two E-type cyclins, cyclins E1 and E2 (collectively referred to as cyclin E), that activate Cdk2 in late G 1 phase. The E-type cyclins are encoded by separate genes, located at chromosomes 19q12 (CCNE1) and 8q22.1 (CCNE2) in humans, but share substantial sequence identity and functional redundancy. The predominant function of cyclin E is believed to be the activation of Cdk2 and consequent effects on cell cycle progression and DNA replication, since both E-type cyclins accelerate the G 1 -to-S-phase transition and most cyclin E-Cdk2 substrates identified to date have roles in cell cycle progression and DNA replication (34). Cyclin E also has crucial, and possibly CDK-independent, functions in the initiation of DNA replication and centrosome duplication (25,26,42), and its deregulation may promote oncogenesis via genomic instability (63) arising through centrosome amplification (35,49,63) or alterations in replication complex assembly (19,45).Overexpression of cyclin E1 in the mouse mammary gland leads to tumor formation at a low frequency (ϳ12%) and long latency (8 to 13 months) (4), although tumorigenesis may be augmented by cooperation with other oncogenic events, particularly p53 inactivation (61). High expression of cyclin E1 protein in breast cancers is strongly correlated with proliferative markers such as elevated Ki67 levels and an elevated mitotic index (6), suggesting that cyclin E1 promotes tumor cell proliferation. This provides good evidence for an association between cyclin E1 and breast oncogenesis, but cyclin E2 has not been indepen...

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Section: Discussionmentioning

confidence: 81%

Estrogen Regulation of Cyclin E2 Requires Cyclin D1 but Not c-Myc

Caldon

Sergio

Schütte

et al. 2009

Molecular and Cellular Biology

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“…Indeed, previous studies have shown that Cyclin D2 can be regulated by multiple mitogenic signals in a number of human cancers, such as leukemia, testicular cancer and ovarian cancer. [20][21][22] Furthermore, whether PITX2 cooperates with other oncogenic signals to upregulate Cyclin D2 in thyroid tumorigenesis remains unclear and warrants further study. Dysregulated (stabilization and translocation of) β-catenin plays a critical role in oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2

Huang¹,

Guigon²,

Fan³

et al. 2010

Cell Cycle

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“…On the other hand, Mullany et al reported that cyclin D1 and D2 differentially regulate transcription and proliferaion in hepatocytes. 18 Second may be that target factors of cyclin D1 and D2 is involved for the interaction between cyclin Ds and p21/p27.…”

confidence: 99%

Differential regulation of cyclin D1 and D2 in protecting against cardiomyocyte proliferation

Tamamori‐Adachi¹,

Goto²,

Yamada³

et al. 2008

Cell Cycle

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Cardiomyocytes withdraw from cell cycle after terminal differentiation due in part to impaired nuclear import of cyclin D1. Thus, we have previously shown that expression of nuclear localization signal-tagged cyclin D1 (D1NLS) and cyclin-dependent kinase 4 promotes cardiomyocyte proliferation both in vitro and in vivo. Here we show that cyclin D2 fails to stimulate cell cycle in cardiomocytes through a mechanism distinct from that of cyclin D1. We demonstrate that cyclin D2 can express in the nucleus much more efficiently than cyclin D1. Cyclin D2, however, was much less effective in activating CDK2 and cell proliferation than cyclin D1 when expressed transiently in the nucleus of cardiomyocytes using nuclear localization signals. Consistent with such an observation, CDK inhibitors p21 cip1 and p27 kip1 remained bound to CDK2 in cells expressing cyclin D2, whereas p21 and p27 were sequestered to cyclin D1 in cells expressing D1NLS. These data suggest that cyclin D2 has weaker affinities to the CDK inhibitors and therefore is less efficient in activating cell cycle than cyclin D1. According to such a notion, double knockdown of p21 and p27 in cells expressing D2NLS induced activation of CDK2/CDC2 and BrdU incorporation to levels similar to those in cells expressing D1NLS. Taken together, our data suggest that distinct mechanisms keep cyclin D1 and cyclin D2 from activating cell cycle in terminally differentiated cardiomyocytes.

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Distinct proliferative and transcriptional effects of the D-type cyclins in vivo

Cited by 76 publications

References 44 publications

Estrogen Regulation of Cyclin E2 Requires Cyclin D1 but Not c-Myc

Estrogen Regulation of Cyclin E2 Requires Cyclin D1 but Not c-Myc

Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2

Differential regulation of cyclin D1 and D2 in protecting against cardiomyocyte proliferation

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