Abstract
In this report we characterize the mechanism of Rac-mediated cyclin D1 gene expression in mouse embryonic fibroblasts. Activated Rac strongly stimulated cyclin D1 gene transcription but did not alter the half-life of cyclin D1 mRNA. Inhibition of NFκB signaling with the IκB super-repressor blocked the Rac-dependent expression of cyclin D1 mRNA, and this effect was selective since ERK-dependent cyclin D1 mRNA induction was minimally affected by super-repressor expression. However, we found that p65 activity in this system was induced by serum and not by activated Rac. Moreover, mouse cyclin D1 promoter-luciferase assays showed that Rac stimulated cyclin D1 gene expression without activating NFκB and that an essential Rac-regulated promoter element is located far upstream or downstream of the cyclin D1 transcription start site. We conclude that, in MEFs, Rac-mediated induction of cyclin D1 mRNA requires activation of a parallel NFκB pathway whereas ERK induces cyclin D1 transcription independent of NFκB.
| Original language | English |
|---|---|
| Pages (from-to) | 1115-1121 |
| Number of pages | 7 |
| Journal | Cell Cycle |
| Volume | 6 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 1 2007 |
Bibliographical note
Funding Information:This work was supported by NIH grants The involvement of the extracellular matrix and cytoskeleton in sustaining ERK GM069064 and CA72639 to R.K.A. activity points to a role for Rho-family GTPases in cyclin D1 regulation. The Rho-family of GTPases has three well-characterized members: Rho, Rac, and cdc42. Each member has different effects on cytoskeletal rearrangement and can be involved in various signaling pathways.11 In the context of cyclin D1 regulation, Rho stimulates sustained ERK activity and mid-G1 cyclin D1 expression while simultaneously inhibiting an alternative Rac-mediated pathway that induces cyclin D1 mRNA in early-G1 phase (1–3 hr after mitogenic stimulation of quiescent fibroblasts).12 Rac-dependent expression of cyclin D1 can also be observed by ectopically expressing an activated Rac allele to overcome the inhibition of endogenous Rac signaling by Rho.12The expression of cyclin D1 by endog-©2007 LANDES BIOSCIENCE enous or ectopic Rac is similar except that ectopic expression of activated Rac results in a constitutive expression of cyclin D1.12 Rac signaling to cyclin D1 is independent of ERK activity,12 but the mechanism by which Rac stimulates cyclin D1 gene expression remains poorly understood.
Funding
This work was supported by NIH grants The involvement of the extracellular matrix and cytoskeleton in sustaining ERK GM069064 and CA72639 to R.K.A. activity points to a role for Rho-family GTPases in cyclin D1 regulation. The Rho-family of GTPases has three well-characterized members: Rho, Rac, and cdc42. Each member has different effects on cytoskeletal rearrangement and can be involved in various signaling pathways.11 In the context of cyclin D1 regulation, Rho stimulates sustained ERK activity and mid-G1 cyclin D1 expression while simultaneously inhibiting an alternative Rac-mediated pathway that induces cyclin D1 mRNA in early-G1 phase (1–3 hr after mitogenic stimulation of quiescent fibroblasts).12 Rac-dependent expression of cyclin D1 can also be observed by ectopically expressing an activated Rac allele to overcome the inhibition of endogenous Rac signaling by Rho.12The expression of cyclin D1 by endog-©2007 LANDES BIOSCIENCE enous or ectopic Rac is similar except that ectopic expression of activated Rac results in a constitutive expression of cyclin D1.12 Rac signaling to cyclin D1 is independent of ERK activity,12 but the mechanism by which Rac stimulates cyclin D1 gene expression remains poorly understood.
| Funders | Funder number |
|---|---|
| National Institutes of Health (NIH) | GM069064 |
| National Childhood Cancer Registry – National Cancer Institute | R01CA072639 |
Keywords
- Cell cycle
- ERK
- G1 phase
- Gene expression
- IκB
- Rho GTPases
- mRNA stability
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology
- Cell Biology