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Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles. Nat Cell Biol 2015 Aug;17(8):1036-48

Date

07/21/2015

Pubmed ID

26192440

Pubmed Central ID

PMC4526313

DOI

10.1038/ncb3210

Scopus ID

2-s2.0-84938694015 (requires institutional sign-in at Scopus site)   56 Citations

Abstract

Robust mechanisms to control cell proliferation have evolved to maintain the integrity of organ architecture. Here, we investigated how two critical proliferative pathways, Myc and E2f, are integrated to control cell cycles in normal and Rb-deficient cells using a murine intestinal model. We show that Myc and E2f1-3 have little impact on normal G1-S transitions. Instead, they synergistically control an S-G2 transcriptional program required for normal cell divisions and maintaining crypt-villus integrity. Surprisingly, Rb deficiency results in the Myc-dependent accumulation of E2f3 protein and chromatin repositioning of both Myc and E2f3, leading to the 'super activation' of a G1-S transcriptional program, ectopic S phase entry and rampant cell proliferation. These findings reveal that Rb-deficient cells hijack and redeploy Myc and E2f3 from an S-G2 program essential for normal cell cycles to a G1-S program that re-engages ectopic cell cycles, exposing an unanticipated addiction of Rb-null cells on Myc.

Author List

Liu H, Tang X, Srivastava A, Pécot T, Daniel P, Hemmelgarn B, Reyes S, Fackler N, Bajwa A, Kladney R, Koivisto C, Chen Z, Wang Q, Huang K, Machiraju R, Sáenz-Robles MT, Cantalupo P, Pipas JM, Leone G

Author

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Binding Sites
Cell Cycle Checkpoints
Cell Proliferation
Chromatin Assembly and Disassembly
E2F Transcription Factors
E2F1 Transcription Factor
E2F2 Transcription Factor
E2F3 Transcription Factor
Epithelial Cells
Female
G1 Phase Cell Cycle Checkpoints
G2 Phase Cell Cycle Checkpoints
Gene Expression Regulation
Genotype
Intestine, Small
Male
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Promoter Regions, Genetic
Proto-Oncogene Proteins c-myc
Retinoblastoma Protein
S Phase Cell Cycle Checkpoints
Signal Transduction
Time Factors
Transcription, Genetic