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/mcb.20.21.8084-8092.2000

Cited by 93 publications

(58 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To test the prediction that RalB regulates NF-kB in UMUC-3 bladder cancer cells, we generated UMUC-3 cells stably expressing a luciferase reporter gene under the control of an NF-kB-responsive promoter. Figure 2a shows that the luciferase activity of these cells was responsive to tumor necrosis factor a, consistent with this promoter being responsive to NF-kB (Henry et al, 2000). When these cells were transfected with siRNA targeting RalA and/or RalB, only the cells with RalB siRNA showed a significant decrease (B30%) in luciferase activity (Figure 2b).…”

Section: Rala and Ralb Signal Via Different Repertoires Of Transcriptsupporting

confidence: 62%

“…While RalA and RalB regulation of NF-kB in NIH 3T3 cells has previously been noted (Henry et al, 2000), it appears that RalB is a more potent regulator of NF-kB than RalA in UMUC-3 cells. This discrepancy may reflect the differences between Ral/NF-kB activities in mouse (NIH3T3) vs human cells (UMUC-3), or reflect different mechanisms in cancer cells.…”

Section: Discussionmentioning

confidence: 66%

“…It has previously been shown that both RalA and RalB regulate cyclin D1 expression in NIH 3T3 cells through activation of NF-kB (Henry et al, 2000). This regulation occurs through unknown effectors, but does not appear to involve the Ral effectors RalBP1 or PLD1.…”

Section: Rala and Ralb Signal Via Different Repertoires Of Transcriptmentioning

confidence: 99%

See 2 more Smart Citations

Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector

2007

View full text Add to dashboard Cite

Although the monomeric GTPases RalA and RalB have been shown to regulate a variety of transcription factors, little is known regarding the differences or similarities in transcriptional programs regulated by RalA compared to RalB. Further, the association of these transcriptional pathways to human carcinogenesis and progression remains unclear. Here, we studied the role of RalA and/ or RalB in transcriptional regulation by combining short interfering RNA depletion of Ral with gene expression profiling via microarray in the human bladder cancer cell line, UMUC-3. A large number of genes were found to be similarly modulated in cells with RalA and RalB depletion, suggesting that RalA and RalB impinge on overlapping transcriptional signaling pathways. However, smaller sets of genes were modulated by depletion of RalA or RalB, indicating that these closely related proteins also regulate nonoverlapping transcriptional pathways. Computational analysis of upstream sequences of genes modulated by Ral depletion identified Ras-responsive element-binding protein (RREB)-1, as a putative Ral transcriptional target, which we verified experimentally. Importantly, as a group, Ral-regulated probe sets identified here were disproportionally represented among those differentially expressed as a function of human bladder transformation. Taken together, these data strongly suggest that Ral family members mediate both common and specific transcriptional programs that are associated with human cancer and identify RREB-1 as a novel transcriptional effector of Ral.

show abstract

Section: Rala and Ralb Signal Via Different Repertoires Of Transcriptsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 66%

See 1 more Smart Citation

Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector

2007

View full text Add to dashboard Cite

show abstract

“…Previously it has been shown that the promoter of the cyclin D1 gene contains an NF-kB binding site needed for expression of cyclin D1 (Guttridge et al, 1999;Henry et al, 2000;Hinz et al, 1999). Because NF-kB is known to be down-regulated by curcumin (Singh and Aggarwal, 1995;Kumar et al, 1998;Plummer et al, 1999;Jobin et al, 1999), it is possible that curcumin affects cyclin D1 expression by affecting the cyclin D1 promoter activity.…”

Section: Curcumin Down-regulates Cyclin D1 Promoter Activitymentioning

confidence: 99%

“…Recently it has been shown that the expression of cyclin D1 is regulated by activation of NF-kB (Guttridge et al, 1999;Henry et al, 2000), which has been shown to control cell growth and the G0/G1-to-Sphase transition (Hinz et al, 1999). Ras-dependent regulation of cyclin D1 transcription has been shown to occur through a NF-kB activation (Joyce et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation

et al. 2002

View full text Add to dashboard Cite

Cyclin D1 is a proto-oncogene that is overexpressed in many cancers including breast and prostate. It plays a role in cell proliferation through activation of cyclin-dependent kinases. Curcumin, a diferuloylmethane, is a chemopreventive agent known to inhibit the proliferation of several breast and prostate cancer cell lines. It is possible that the effect of curcumin is mediated through the regulation of cyclin D1. In the present report we show that inhibition of the proliferation of various prostate, breast and squamous cell carcinoma cell lines by curcumin correlated with the down-regulation of the expression of cyclin D1 protein. In comparison, the down-regulation by curcumin of cyclin D2 and cyclin D3 was found only in selective cell lines. The suppression of cyclin D1 by curcumin led to inhibition of CDK4-mediated phosphorylation of retinoblastoma protein. We found that curcumin-induced down-regulation of cyclin D1 was inhibited by lactacystin, an inhibitor of 26S proteosome, suggesting that curcumin represses cyclin D1 expression by promoting proteolysis. We found that curcumin also down-regulated mRNA expression, thus suggesting transcriptional regulation. Curcumin also inhibited the activity of the cyclin D1 promoter-dependent reporter gene expression. Overall our results suggest that curcumin down-regulates cyclin D1 expression through activation of both transcriptional and post-transcriptional mechanisms, and this may contribute to the antiproliferative effects of curcumin against various cell types.

show abstract

Transport of glutathione conjugates and chemotherapeutic drugs by RLIP76 (RALBP1): A novel link between G‐protein and tyrosine kinase signaling and drug resistance

Awasthi

Singhal

Sharma

et al. 2003

Intl Journal of Cancer

109

177

View full text Add to dashboard Cite

Our studies have shown that RLIP76 (RALBP1), a 76 kDa Ral-binding, Rho/Rac-GAP and Ral effector protein, is a novel multispecific transporter of xenobiotics as well as GS-Es. Like previously characterized ABC transporters, it mediates ATP-dependent transport of structurally unrelated amphiphilic xenobiotics and displays inherent ATPase activity, which is stimulated by its substrate allocrites. It does not have significant sequence homology with ABC transporters and differs from the ABC transporters in several other important aspects, including (i) lack of any close homologs in humans, (ii) lack of a classical Walker domain, (iii) integral membrane association without clearly defined transmembrane domains and (iv) its role as a direct link to Ras/Ral/Rho and EGF-R signaling through its multifunctional nature, including GAP activity, regulation of exocytosis as well as clathrin-coated pit-mediated receptor endocytosis. Its multifunctional nature derives from the presence of multiple motifs, including a Rho/Rac GAP domain, a Ral effector domain binding motif, 2 distinct ATP-binding domains, a H ؉ -ATPase domain, PKC and tyrosine kinase phosphorylation sites and the ability to undergo fragmentation into multiple smaller peptides which participate as components of macromolecular functional complexes. One of the physiologic functions of RLIP76 is regulation of intracellular concentration of the electrophilic intermediates of oxidative lipid metabolism by mediating efflux of GS-E formed from oxidative degradation of arachidonic acid, including leukotrienes and the 4HNE-GSH conjugate. RLIP76-mediated transport of amphiphilic chemotherapeutic agents such as anthracyclines and vinca alkaloids as well as GS-E produced during oxidative metabolism places this multifunctional protein in a central role as a resistance mechanism for preventing apoptosis caused by chemotherapeutic agents and a variety of external/internal stressors, including oxidative stress, heat shock and radiation. GSH 1 is a ubiquitous nucleophilic sulfhydryl tripeptide, which protects cells from damage caused by endogenously generated (endobiotic) as well as exogenous (xenobiotic) electrophilic and oxidant chemicals. GSH can serve as an electron donor for reduction of oxidant species, including highly toxic lipid hydroperoxides generated as a common toxic intermediate during any oxidative stress (chemical, heat, radiation) of sufficient magnitude. Reduction of these highly reactive species terminates lipid peroxidation, a chain reaction that can markedly amplify the damaging effects of oxidative injury. Through formation of thioether conjugates, GSH also functions as a scavenger of the exogenous alkylating agents, as well as of less reactive but still quite toxic alkylating electrophiles generated as downstream products of lipid peroxidation. Formation of GS-Es occurs spontaneously, as well as through glutathione S-transferase-catalyzed reactions, and is the first step in the metabolism of electrophiles to mercapturates. In addition to being precursors of ...

show abstract

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

Abstract: Ral GTPases have been implicated as mediators of Ras-induced signal transduction from observations that

Cited by 93 publications

References 66 publications

Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector

Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector

Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation

Transport of glutathione conjugates and chemotherapeutic drugs by RLIP76 (RALBP1): A novel link between G‐protein and tyrosine kinase signaling and drug resistance

Contact Info

Product

Resources

About