Cyclin D1 determines mitochondrial function in vivo.
The cyclin D1 gene encodes a regulatory subunit of the holoenzyme that phosphorylates and inactivates the pRb tumor suppressor to promote nuclear DNA synthesis. cyclin D1 is overexpressed in human breast cancers and is sufficient for the development of murine mammary tumors. Herein, cyclin D1 is shown to perform a novel function, inhibiting mitochondrial function and size. Mitochondrial activity was enhanced by genetic deletion or antisense or small interfering RNA to cyclin D1. Global gene expression profiling and functional analysis of mammary epithelial cell-targeted cyclin D1 antisense transgenics demonstrated that cyclin D1 inhibits mitochondrial activity and aerobic glycolysis in vivo. Reciprocal regulation of these genes was observed in cyclin D1-induced mammary tumors. Cyclin D1 thus integrates nuclear DNA synthesis and mitochondrial function.
Sakamaki
Toshiyuki
T
Departments of Cancer Biology, Thomas Jefferson University, BLSB, Room 1050, 233 South 10th Street, Philadelphia, PA 19107, USA.
Casimiro
Mathew C
MC
Ju
Xiaoming
X
Quong
Andrew A
AA
Katiyar
Sanjay
S
Liu
Manran
M
Jiao
Xuanmao
X
Li
Anping
A
Zhang
Xueping
X
Lu
Yinan
Y
Wang
Chenguang
C
Byers
Stephen
S
Nicholson
Robert
R
Link
Todd
T
Shemluck
Melvin
M
Yang
Jianguo
J
Fricke
Stanley T
ST
Novikoff
Phyllis M
PM
Papanikolaou
Alexandros
A
Arnold
Andrew
A
Albanese
Christopher
C
Pestell
Richard
R
D000818:Animals; D001483:Base Sequence; D019938:Cyclin D1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006019:Glycolysis; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000235:genetics; D008321:Mammary Glands, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019938:Cyclin D1; D004247:DNA; D006593:Hexokinase