Formation and Activation of a Cyclin E-cdk2 Complex During the G
            <sub>1</sub>
            Phase of the Human Cell Cycle

Koff, Andrew; Giordano, Antonio; Desai, Dev M.; Yamashita, Katsumi; Jw, Harper; Elledge, Stephen J.; Nishimoto, Tetsuya; Morgan, David; Franza, B. R.; Jm, Roberts

doi:10.1126/science.1388288

Cited by 982 publications

(639 citation statements)

References 17 publications

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“…As shown in Figure 3a, TIMP-1 overexpression lead to a significant decrease in the cyclin D 1 level, a G 1 cyclin critical for cell cycle entry and G 1 progression (Motokura and Arnold, 1993;Hatakeyama et al, 1994), whereas it induced the level of cyclin E1 expression, a late G 1 cyclin critical for the cell cycle progression into the S phase Hinds et al, 1992;Koff et al, 1992). Since kinase activities of cyclin complexes are regulated by CDKIs, we also examined the effects of TIMP-1 overexpression on CDKI expression.…”

Section: Resultsmentioning

confidence: 99%

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

et al. 2006

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Increasing evidence suggests that tissue inhibitor of metalloproteinases-1 (TIMP-1) can directly regulate cell growth and apoptosis independent of its matrix metalloproteinases (MMPs)-inhibitory activity. While TIMP-1's antiapoptotic activity has been well demonstrated, conflicting data has been reported regarding TIMP-1's role in growth regulation. Here we show that TIMP-1 reduces the growth rate of human breast epithelial (MCF10A) cells by inducing cell cycle arrest at G 1 . TIMP-1-mediated cell cycle arrest is associated with its downregulation of cyclin D 1 and upregulation of p27 KIP1 , resulting in inhibition of cyclin-dependent kinase activity necessary for phosphorylation of the tumor suppressor retinoblastoma protein. We further show that TIMP-1 modulation of cyclin D 1 and p27 KIP1 is achieved through TIMP-1-mediated differential regulation of protein stability independent of growth factor signaling. We also show that TIMP-1-mediated differential regulation of cyclin D 1 and p27 KIP1 is independent of cell adhesion signaling. Whereas approximately 50% of MCF10A cells with reduced TIMP-1 expression underwent cell death following loss of cell adhesion (anoikis), TIMP-1 overexpressing cells remained viable with prominent cell cycle arrest without detectable cell death. Taken together, we propose that TIMP-1-mediated cell survival independent of cell adhesion is accompanied with cell cycle arrest in human breast epithelial cells, although cell cycle regulation may not be a prerequisite for TIMP-1 regulation of apoptosis in general.

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Section: Resultsmentioning

confidence: 99%

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

et al. 2006

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“…43,44 Miller et al 45 reported that miR-221/222 expressions were upregulated in endocrine therapy-resistant luminaltype breast cancer cells. MiR-221/222 are negative regulators of p27 kip1 , a cell cycle inhibitor and tumor suppressor, [46][47][48][49][50] and upregulated expressions of these miRNAs and significant reductions in p27 kip1 levels have been reported in tamoxifen-resistant breast cancer cells; therefore, miR-221/222 might regulate tamoxifen sensitivity via the direct targeting of p27 kip1 . 51,52 Pichiorri et al 53 found that miR-221/222 expressions were modulated by nucleolin at the post-transcriptional level.…”

Section: Mirna In Hormone Receptor-positive/her2-negative Breast Cancermentioning

confidence: 99%

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

et al. 2016

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MicroRNAs (miRNAs) are short non-coding RNAs that regulate the function of target genes at the post-transcriptional phase. miRNAs are considered to have roles in the development, progression and metastasis of cancer. Recent studies have indicated that particular miRNA signatures are correlated with tumor aggressiveness, response to drug therapy and patient outcome in breast cancer. On the other hand, in routine clinical practice, the treatment regimens for breast cancer are determined based on the intrinsic subtype of the primary tumor. Previous studies have shown that miRNA expression profiles of each intrinsic subtypes of breast cancer differ. In hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, miRNA expressions are found to be correlated with endocrine therapy resistance, progesterone receptor expression and heat shock protein activity. Some miRNAs are associated with resistance to HER2-targeted therapy and HER3 expression in HER2-positive breast cancer. In triple-negative breast cancer, miRNA expressions are found to be associated with BRCA mutations, immune system, epithelial-mesenchymal transition, cancer stem cell properties and androgen receptor expression. As it has been clarified that the expression levels and functions of miRNA differ among the various subtypes of breast cancer, and it is necessary to take account of the characteristics of each breast cancer subtype during research into the roles of miRNA in breast cancer. In addition, the discovery of the roles played by miRNAs in breast cancer might provide new opportunities for the development of novel strategies for diagnosing and treating breast cancer.

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“…Inactivation of pRb repression of E2F results in the transcription of Cyclin E, and Cyclin A, as well as E2F itself prior to the G1/S transition stage (Woo and Poon, 2003). At the onset of S phase, Cdk2 (Cdc28 in yeast) is activated by expressed Cyclin E subunits, which then continues the phosphorylation of pRb (Koff et al, 1991;Koff et al, 1992). Accumulating Cyclin A generated from the pRb/E2F…”

Section: A Brief Description Of Cell Cycle Progression From G1 and S mentioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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Formation and Activation of a Cyclin E-cdk2 Complex During the G ₁ Phase of the Human Cell Cycle

Cited by 982 publications

References 17 publications

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

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Formation and Activation of a Cyclin E-cdk2 Complex During the G 1 Phase of the Human Cell Cycle

Cited by 982 publications

References 17 publications

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27KIP1 protein

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

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Formation and Activation of a Cyclin E-cdk2 Complex During the G ₁ Phase of the Human Cell Cycle