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Background
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Pediatric
cancer retinoblastoma and the formation of other human tumors can be
attributed to mutations in the retinoblastoma tumor suppressor gene. The
retinoblastoma tumor suppressor gene product, known as Rb or pRb, regulates
differentiation, apoptosis and cell cycle control by coordinating the cell
cycle, at G1/S, with transcriptional machinery that includes the
heterodimeric E2F family. During G1, cyclin D (D1, D2, D3)-dependent
kinase-mediated phosphorylation of Rb at Ser 795 marks the conversion of Rb
from a transcriptionally repressive, hypophosphorylated state to an inactive,
phosphorylated state, which may be sustained through mitosis by differential
phosphorylation of up to 16 putative serine or threonine residues, including
Ser 249/Thr 252, Thr 373, Thr 356, Ser 780, Ser 807/Ser 811 and Thr 821/Thr
826. Hypophosphorylated Rb represses the transcription of genes controlling
cell cycle through direct protein-protein interactions, by binding and
inactivating the promoters of transcription factors, and through recruitment
of histone deacetylase, which deacetylates promoter regions and enhances
nucleosome formation, thereby masking transcription enhancing cis elements.
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