E2F-dependent induction of p14ARF during cell cycle re-entry in human T cells.
The ARF protein, encoded by alternate exon usage within the CDKN2A locus, provides a link between the retinoblastoma (pRb) and p53 tumor suppressor pathways. Agents that disable pRb or otherwise impinge on the E2F family of transcription factors induce expression of ARF, resulting in stabilization of p53 and activation of p53-regulated genes. However, in some cell types ARF is not induced upon cell cycle re-entry, as expected of a conventional E2F target gene, leading to the suggestion that the ARF promoter only responds to supra-physiological or aberrant levels of E2F. These properties have recently been attributed to a variant E2F binding site but attempts to map specific response elements within the ARF promoter have generally yielded confusing answers. Here we show that in IL2-dependent T-lymphocytes, ARF expression is induced as cells progress from G(0) into S phase, in parallel with other bona fide E2F target genes. This is accompanied by increased association of E2F1 with the endogenous ARF promoter. Our findings suggest that the ability of ARF to register normal proliferative cues depends on the levels of E2F generated in different settings and argue against the idea that it reacts exclusively to oncogenic signals.
del Arroyo
Ana Gutierrez
AG
Cancer Research UK, London Research Institute, Lincoln's Inn Fields, London, UK.
El Messaoudi
Selma
S
Clark
Paula A
PA
James
Marion
M
Stott
Francesca
F
Bracken
Adrian
A
Helin
Kristian
K
Peters
Gordon
G
D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D050684:E2F Transcription Factors / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis* / Q000235:genetics*
D050684:E2F Transcription Factors; D025803:Tumor Suppressor Protein p14ARF