Year: 2010
Type: article
Abstract: The retinoblastoma tumor suppressor gene (RB1; encoding RB) is often cited as a gatekeeper, whose inactivation -direct or indirect -is a rate-limiting step for tumor initiation.However, in this issue of the JCI, Sharma et al. show that RB1 loss is a late event in human prostate cancer that is coincident with the emergence of castrate-resistant metastatic disease.This role for RB1 was linked to both E2F transcription factor 1-driven upregulation of the androgen receptor (AR) and increased recruitment of the AR to target gene promoters.This unexpected function for RB1 in late-stage cancer calls upon us to reassess the significance of RB1 inactivation in other cancers in terms of its timing, function in disease etiology, and relevance for cancer therapy.The retinoblastoma pathway paradigm is challenged The canonical function of the retinoblastoma protein (RB; encoded by RB1), elucidated primarily through the manipulation of human tumor cell lines and genetically engineered mouse models, has established a key role for RB in repressing the transcriptional activity of the so-called activator class of E2F transcription factors (E2F1-E2F3) (1, 2).E2Fs regulate the expression of a growing number of genes but are best defined for their transcriptional regulation of genes required for cell cycle, including genes involved in DNA replication, nucleotide synthesis, and checkpoint control.Initial work indicated that regulation of E2F activity by RB occurred primarily at the transition between the G1 and S phases of the cell cycle.However, there is growing appreciation that RB can be activated in S-phase by dephosphorylation in response to stresses, such as oxidative stress, and that RB regulates the mitotic checkpoint by modulating the expression of E2F target genes involved in chromosome segregation and cytokinesis (2).The phosphorylation state and activity of RB is sensitive to environmental cues mediated largely through the activity of cyclindependent kinase 4 (CDK4) and CDK6 complexed to D-type cyclins.Phosphorylation of RB on key residues inhibits binding to E2Fs and also derepresses CDK2 complexed to E-type cyclins, resulting in further RB phos-
DOI: 10.1172/jci45406
Author: Kay F. Macleod
Institution: University of Chicago
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Award: G6632223665
OpenAlex ID: W2095776712