SurveyNF-κB and cell-cycle regulation: the cyclin connection
Section snippets
The NF-κB protein family
The NF-κB/Rel family of transcription factors are active in inflammatory and immune cell response, cell cycle regulation, differentiation and protection from apoptosis (reviewed in refs. [1] and [2]. The mammalian members of the NF-κB/Rel family are Rel-A (p65), Rel-B, c-Rel, NF-κB1 (p50/p105) and NF-κB2 (p52/p100) [3], [4], [5], [6], [7], [8]. They all have an extended amino-terminal region knows as the Rel homology domain (RHD), which incorporates a leucine zipper dimerization domain, a
Cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors in cell growth regulation
The cyclin-dependent kinases (CDK's) are important regulators of the mammalian cell cycle (for reviews see [91]). CDK activity is modulated by mitogens and growth factors, by pathways that include NF-κB factors. Escape of CDK's from normal regulation, or escape of downstream events from CDK control, frequently accompanies cellular transformation. The activities of CDK4, CDK6, CDK2 and the Cdc2 kinase are expressed differentially during the cell cycle, in response to changes in the abundance of
Cyclin-dependent kinase inhibitors
CDK complexes are subject to regulation by proteins of two families. The Ink4 proteins act to dissociate cyclin D1/CDK4/CDK6 complexes [127], [128], [129], whilst the p2l family proteins inhibit CD1K activity in some circumstances [130], [131]. The Ink4 family includes p16Ink4a, p15Ink4b, p18Ink4c and p19Ink4d. Additionally, the p16Ink4a gene locus also encodes a further protein, p19ARF (pl4ARF in human cells) [132] in an alternate reading frame, which shares CD1K inhibitory activity. In the
Cyclin-dependent kinase function
The CDK's themselves regulate cell-cycle controlling genes and proteins through kinase functions and through direct protein-protein interactions (reviewed in ref. [91]). Prominent amongst these are interactions with transcription factors. For example, cyclin A/CDK2 and cyclin B/Cdc2 phosphorylate p53, enhancing transactivation through the p53 response element [152]. Cyclin A/CDK2 phosphorylation of B-myb enhances transcriptional activity through the MBS site [153]. Conversely, Cyclin A/CDK2
NF-κB in mitogen-stimulated cell growth
Variations in NF-κB activity through the cell cycle, enhanced activity after mitogenic stimulation, the v-Rel oncogene and apoptosis of Rel-A-deficient cells together drew attention to a role for NFκB factors in cell growth and survival. The association between normal growth and NF-κB activation has been noted in many cells and tissues. Enhanced NF-κB is apparent during the G0/G1 transition in fibroblasts [164] and is induced by mitogenic stimuli, including serum, in G0 arrested 3T3 fibroblasts
NF-κB and growth of transformed cells
Disordered expression of NF-κB family proteins in mammalian and avian neoplasia has drawn attention to roles in transformation, both through abnormal NF-κB proteins and though oncogenic protein activation of NF-κB signaling pathways. V-Rel was initially identified in transformed avian hemopoietic cells and is an oncogenic NF-κB family member which is encoded by the Rev-T avian retrovirus (for review see ref. [198]). Abnormal NF-κB family proteins also occur in a small percentage of human B and
Oncogene activation of NF-κB
Activation of NF-κB occurs in cells transformed by several classical oncoproteins including transforming Ras and Rac, the chimeric Bcr-Abl oncoproteins and transforming viral proteins. NF-κB is required for focus formation by NIH 3T3 cells expressing transforming Ras [68]. The observations that Ras activated cyclin D1 [107], and that this was required for Ras-induced transformation [205], [206] suggested that cyclin D1 itself may be a target of NF-κB activity. Similarly, transforming mutants of
NF-κB increases cyclin D1 expression
Observations on transformed cells and cells undergoing normal mitogen-stimulated growth, implicate proteins of the NF-κB family in cell cycle regulation, through actions on the CDK/CKI system. Experiments in many cell types now indicate that NF-κB acts through increasing the abundance of cyclin D1 and thus the activity of the cyclin D1 kinase holoenzyme complex. The role of NF-κB factors in controlling the cell cycle and cyclin D1 has been well shown in investigations that used the IκB “super
NF-κB, cyclin D1 and cell differentiation
Terminal differentiation of mammalian cells is generally accompanied by cessation of growth. In vitro myogenic differentiation models have demonstrated that NF-κB has roles in both cell cycling and suppression of terminal differentiation. Enhanced expression of cyclin D1 is central to both roles. Like other cell types, C2C12 myoblasts express the NF-κB1/Rel-A heterodimer whilst proliferating, and proliferate more slowly if NF-κB is inhibited [104]. Inducing myogenic differentiation, however,
NF-κB signaling in oncogene-transformed cells
It is therefore established that NF-κB factors enhance cell cycle progression in widely different cells types after exposure to mitogenic stimuli, through activating cyclin D1 transcription. Activation of NF-κB also occurs in cells transformed by several classical oncoproteins, including transforming Ras and Rac, the chimeric Bcr-Abl oncoproteins and transforming viral proteins, [68], [107], [205], [206], [207], [208], [209]. The observations have prompted examination of NF-κB-cyclin D1 pathway
Other NF-κB interactions with the cyclin/CDK/CKI system
There is also some evidence that the cyclin A promoter may be transcriptionally activated by NF-κB, although it has no consensus NF-κB sites [69]. Consistent with this, IκB-SR suppressed cyclin A abundance when expressed in myoblastic cell [104]. IκB-SR does not affect CDK2 abundance, but the rise in CDK2 activity which normally accompanies release from G0 is delayed in fibroblasts expressing IκB-SR [103]. This may be related to reduced cyclin A abundance. Interestingly, though, the cyclin
Conclusion
Increased NF-κB activity during growth of mitogen-stimulated and transformed cells has therefore been linked to cell cycle progression through transcriptional activation of the cyclin D1 gene, leading to increased abundance of cyclin D1 and increased activity of cyclin D1 kinase. Although this pathway has been observed in multiple cell types and under different conditions, it is unlikely to be the only link between NF-κB factor activity and cell cycle progression. Future research will tell us
Acknowledgements
We are grateful to Drs. M. Horwitz, and J. Friedman for helpful discussions. This work was supported in part by RO1CA70897, RO1CA75503, 5-P30-CA13330-26 (R.G.P.).
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