B-MYB is essential for normal cell cycle progression and chromosomal stability of embryonic stem cells.
BACKGROUND
The transcription factor B-Myb is present in all proliferating cells, and in mice engineered to remove this gene, embryos die in utero just after implantation due to inner cell mass defects. This lethal phenotype has generally been attributed to a proliferation defect in the cell cycle phase of G1.


RESULTS
In the present study, we show that the major cell cycle defect in murine embryonic stem (mES) cells occurs in G2/M. Specifically, knockdown of B-Myb by short-hairpin RNAs results in delayed transit through G2/M, severe mitotic spindle and centrosome defects, and in polyploidy. Moreover, many euploid mES cells that are transiently deficient in B-Myb become aneuploid and can no longer be considered viable. Knockdown of B-Myb in mES cells also decreases Oct4 RNA and protein abundance, while over-expression of B-MYB modestly up-regulates pou5f1 gene expression. The coordinated changes in B-Myb and Oct4 expression are due, at least partly, to the ability of B-Myb to directly modulate pou5f1 gene promoter activity in vitro. Ultimately, the loss of B-Myb and associated loss of Oct4 lead to an increase in early markers of differentiation prior to the activation of caspase-mediated programmed cell death.


CONCLUSIONS
Appropriate B-Myb expression is critical to the maintenance of chromosomally stable and pluripotent ES cells, but its absence promotes chromosomal instability that results in either aneuploidy or differentiation-associated cell death.
Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
Kirill V
KV
Tarasov
Yelena S
YS
Tarasova
Wai Leong
WL
Tam
Daniel R
DR
Riordon
Steven T
ST
Elliott
Gabriela
G
Kania
Jinliang
J
Li
Satoshi
S
Yamanaka
David G
DG
Crider
Gianluca
G
Testa
Ronald A
RA
Li
Bing
B
Lim
Colin L
CL
Stewart
Yie
Y
Liu
Jennifer E
JE
Van Eyk
Robert P
RP
Wersto
Anna M
AM
Wobus
Kenneth R
KR
Boheler
D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation; D043171:Chromosomal Instability; D053595:Embryonic Stem Cells / Q000166:cytology*; D020570:Genes, myb; D051379:Mice; D011123:Polyploidy; D011401:Promoter Regions, Genetic; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000502:physiology*
D020598:Proto-Oncogene Proteins c-myb