NF-kappaB1 can inhibit v-Abl-induced lymphoid transformation by functioning as a negative regulator of cyclin D1 expression.
Mounting evidence implicates deregulated Rel/NF-kappaB signaling as a common feature of lymphoid malignancies. Despite the fact that they promote the survival and proliferation of normal lymphocytes, the underlying mechanisms by which various Rel/NF-kappaB proteins with different transcriptional regulatory capacities might facilitate transformation remain to be established. Here we show that the proliferation and tumorigenicity of Abelson murine leukemia virus (A-MuLV)-transformed pre-B cells are enhanced in the absence of NF-kappaB1 and that this coincides with elevated levels of cyclin D1. Support for a link between cyclin D1 expression and v-Abl transformation came from the finding that proliferation of transformed pre-B cells was reduced in the absence of cyclin D1, while enforced cyclin D1 expression increased the proliferation and tumorigenicity of wild-type transformants. A reduction in endogenous cyclin D1 levels that coincided with NF-kappaB1 transgene reversal of enhanced nfkb1(-/-) pre-B-cell transformation, coupled with NF-kappaB1 inhibition of v-Abl-induced kappaB-dependent murine cyclin D1 transcription, lends support to a model in which v-Abl-induced cyclin D1 transcription in transformed pre-B cells is controlled by Rel/NF-kappaB dimers with different activities.
Nakamura
Yukio
Y
The Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Victoria 3050, Australia.
Grumont
Raelene J
RJ
Gerondakis
Steve
S
D000011:Abelson murine leukemia virus / Q000472:pathogenicity; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001854:Bone Marrow Cells / Q000473:pathology / Q000821:virology; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000378:metabolism*; D019281:Dimerization; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D016313:Genes, abl / Q000235:genetics; D007942:Leukemia, Experimental / Q000209:etiology* / Q000473:pathology; D008221:Lymphoid Tissue / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000502:physiology*; D021122:Protein Subunits; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015996:Survival Rate; D013945:Thymoma / Q000209:etiology / Q000473:pathology
D016328:NF-kappa B; D021122:Protein Subunits; D020569:Proto-Oncogene Proteins c-rel; D019938:Cyclin D1