Ral GTPases Contribute to Regulation of Cyclin D1 through Activation of NF-κB

Henry, Dale O.; Moskalenko, Serge A.; Kaur, Kiran; Fu, Maofu; Pestell, Richard G.; Camonis, Jacques; White, Michael A.

doi:10.1128/.20.21.8084-8092.2000

Cited by 24 publications

(25 citation statements)

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“…A role for Ral in proliferation has been reported and the Ras/Ral pathway has been suggested to play a role in DNA synthesis and eventually cell transformation (Wolthuis and Bos, 1999). Expression of activated Ral has been shown to be sufficient to induce activation of NF‐κB gene expression and cyclin D1 transcription, two key convergent points for mitogenic and survival signalling (Henry et al ., 2000). Thus, if LT‐IP82‐induced apoptosis is linked to its glucosylating effect on a small G‐protein, Ral could be candidate and this hypothesis requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Lethal toxin fromClostridium sordelliiinduces apoptotic cell death by disruption of mitochondrial homeostasis in HL-60 cells

Petit

Bréard

Montalescot

et al. 2003

Cellular Microbiology

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SummaryLethal toxin (LT) from Clostridium sordellii (strain IP82) inactivates in glucosylating the small GTPases Ras, Rap, Ral and Rac. In the present study we show that LT-IP82 induces cell death via an intrinsic apoptotic pathway in the myeloid cell-line HL-60. LT-IP82 was found to disrupt mitochondrial homeostasis as characterized by a decrease in mitochondrial transmembrane potential and cardiolipin alterations, associated with the release of cytochrome c in the cytosol. Time-course studies of caspase activation revealed that caspase-9 and caspase-3 were activated before caspase-8. Moreover, although LT-IP82-induced cell death was abrogated by caspase-inhibitors, these inhibitors did not suppress mitochondrial alterations, indicating that caspase activation occurs downstream of mitochondria. Protection of mitochondria by Bcl-2 overexpression prevented mitochondrial changes as well as apoptosis induction. Furthermore, evidence is provided that LT-IP82-induced apoptosis is not a consequence of cortical actin disorganization, suggesting that Rac inactivation does not initiate the apoptotic process. Cell exposure to LT-IP82 leads to a co-localization of the toxin with a mitochondrial marker within 2 h. Therefore, we suggest that LT-IP82 could act at the mitochondrion level independently of its enzymatic effect on small GTPases.

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Section: Discussionmentioning

confidence: 99%

Lethal toxin fromClostridium sordelliiinduces apoptotic cell death by disruption of mitochondrial homeostasis in HL-60 cells

Petit

Bréard

Montalescot

et al. 2003

Cellular Microbiology

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“…In an alternative Ras effector pathway, the Ral GTPase is activated and reinforces particular regulatory events mediated by the Ras/Erk cascade. Ral activates NF‐κB which subsequently binds to response elements in the cyclin D1 promoter to stimulate transcription of this gene [Henry et al, 2000]. Ral also induces phosphorylation of Forkhead family transcription factors (FOXO) to prevent their nuclear entry, which in turn prevents their transcriptional regulation of p21 and p27 [Coleman et al, 2004].…”

Section: Signalling To the Cell‐cycle Machinerymentioning

confidence: 99%

Cell cycle control in breast cancer cells

Caldon

Daly

Sutherland

et al. 2005

J of Cellular Biochemistry

197

139

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In breast cancer, cyclins D1 and E and the cyclin-dependent kinase inhibitors p21 (Waf1/Cip1)and p27 (Kip1) are important in cell-cycle control and as potential oncogenes or tumor suppressor genes. They are regulated in breast cancer cells following mitogenic stimuli including activation of receptor tyrosine kinases and steroid hormone receptors, and their deregulation frequently impacts on breast cancer outcome, including response to therapy. The cyclindependent kinase inhibitor p16 (INK4A) also has a critical role in transformation of mammary epithelial cells. In addition to their roles in cell cycle control, some of these molecules, particularly cyclin D1, have actions that are not mediated through regulation of cyclin-dependent kinase activity but may be important for loss of proliferative control during mammary oncogenesis. J. Cell. Biochem. 97: 261-274, 2006. ß 2005 Wiley-Liss, Inc.Key words: cyclin D1; cyclin E; CDK inhibitors; steroid hormones; receptor tyrosine kinasesThe identification of cyclins in the 1980s revolutionized the cell-cycle field and the subsequent functional analysis of cyclins and CDKs provided an unprecedented opportunity to gain a molecular understanding of the cell-cycle machinery, its regulation in normal physiology, and its deregulation during oncogenesis. In the context of breast cancer, cyclins D1 and E were quickly established as early response genes following treatment with known regulators of proliferation including steroids and mitogenic growth factors. Complementary studies showed that these cyclins were deregulated in breast cancer. As the complexity of regulation of CDK activity was revealed, it also became apparent that the cell-cycle machinery was deregulated at multiple levels in breast cancer cells. There is now so much information on the regulation and function of the cell-cycle machinery in breast cancer cells that we have necessarily been selective in the areas covered in this review. We have concentrated here on the cyclins and CDK inhibitors that have been most extensively studied as regulators of the cell cycle in breast cancer cells, as putative mammary oncogenes or tumor suppressor genes, and as potential markers of therapeutic response or outcome: cyclins D1 and E1, and the CDK inhibitors p27 (Kip1), p21 (WAF1/Cip1), and p16 (INK4A). Although this review focuses on cyclins and CDK inhibitors, there are other cell-cycle regulators of known importance in breast cancer, notably the proto-oncogene c-Myc, which has recently been reviewed in this context [Jamerson et al., 2004]. CELL-CYCLE CONTROL MECHANISMSThe cell cycle comprises a series of tightly controlled events that drive the replication of DNA and cell division. It is divided into several phases: preparation for (G 1 phase), and execution of, DNA synthesis (S phase), a second gap phase (G 2 ), and mitosis (M). Quiescence (G 0 ) is a ß 2005 Wiley-Liss, Inc.

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“…Overexpression of cyclin D1 has been noted in over 50% of human breast tumors of all histological types [20–22]. Cyclin D1 overexpression is found at the earliest stages of breast cancer progression such as ductal carcinoma in situ and maintained in all stages of metastasis [23].…”

Section: Introductionmentioning

confidence: 99%

“…Cyclin D1 overexpression is found at the earliest stages of breast cancer progression such as ductal carcinoma in situ and maintained in all stages of metastasis [23]. The expression of cyclin D1 is regulated by diverse signaling cascades [20–23]. In addition, upregulation of cyclin D1 by estrogen receptor‐α (ERα) signaling is accompanied by an increased proliferative response in breast cancer cells [24,25], as ERα‐stimulated proliferation could be effectively blocked by antisense cyclin D1 [25].…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells

et al. 2004

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Recent studies have shown that p21-activated kinase 1 (Pak1) phosphorylates estrogen receptor-(ER) at Ser 305 and also promotes its transactivation function. Here, we sought to investigate whether substitution of serine 305 in ER with glutamic acid (ER-S305E), which mimics the phosphorylation state, would influence the status of ER-target genes. To explore this possibility, we generated clones overexpressing ER-S305E in ER-negative MDA-MB-231 cells and analyzed the status of ERregulated genes using a gene array. Results indicated that the expression of ER-S305E is sufficient to upregulate the expression of a few but not all ER-regulated genes, i.e., cyclin D1 and zinc finger protein 147 (estrogen-responsive finger protein), while there was no significant change in the expression of remaining genes on the array. In addition, we found an increased expression as well as nuclear accumulation of cyclin D1 protein in MDA-MB-231 cells expressing ER-S305E as compared to the level of cyclin D1 in MDA-MB-231 cells expressing WT-ER or pcDNA. Furthermore, ER-S305E, but not mutation of ER-S305 to alanine, enhanced the cyclin D1 promoter activity. These findings suggest that ER activation at S305 is sufficient to upregulate the expression of cyclin D1, an ER-regulated gene that is implicated in the progression of breast cancer. Phosphorylation of ER by Pak1 or its upstream regulators could upregulate the expression of a subset of ER-target genes in a ligand-independent manner and hence, might contribute toward the development of hormone independence in breast cancer cells.

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Ral GTPases Contribute to Regulation of Cyclin D1 through Activation of NF-κB

Cited by 24 publications

References 0 publications

Lethal toxin fromClostridium sordelliiinduces apoptotic cell death by disruption of mitochondrial homeostasis in HL-60 cells

Lethal toxin fromClostridium sordelliiinduces apoptotic cell death by disruption of mitochondrial homeostasis in HL-60 cells

Cell cycle control in breast cancer cells

Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells

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