Back to Search
Start Over
Sequential inductions of the ZEB1 transcription factor caused by mutation of Rb and then Ras proteins are required for tumor initiation and progression.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2013 Apr 19; Vol. 288 (16), pp. 11572-80. Date of Electronic Publication: 2013 Feb 26. - Publication Year :
- 2013
-
Abstract
- Rb1 restricts cell cycle progression, and it imposes cell contact inhibition to suppress tumor outgrowth. It also triggers oncogene-induced senescence to block Ras mutation. Loss of the Rb1 pathway, which is a hallmark of cancer cells, then provides a permissive environment for Ras mutation, and Ras is sufficient for invasive tumor formation in Rb1 family mutant mouse embryo fibroblasts (MEFs). These results demonstrate that sequential mutation of the Rb1 and Ras pathways comprises a tumor initiation axis. Both Rb1 and Ras regulate expression of the transcription factor ZEB1, thereby linking tumor initiation to the subsequent invasion and metastasis, which is induced by ZEB1. ZEB1 acts in a negative feedback loop to block expression of miR-200, which is thought to facilitate tumor invasion and metastasis. However, ZEB1 also represses cyclin-dependent kinase (cdk) inhibitors to control the cell cycle; its mutation in MEFs leads to induction of these inhibitors and premature senescence. Here, we provide evidence for two sequential inductions of ZEB1 during Ras transformation of MEFs. Rb1 constitutively represses cdk inhibitors, and induction of ZEB1 when the Rb1 pathway is lost is required to maintain this repression, allowing for the classic immortalization and loss of cell contact inhibition seen when the Rb1 pathway is lost. In vivo, we show that this induction of ZEB1 is required for Ras-initiated tumor formation. ZEB1 is then further induced by Ras, beyond the level seen with Rb1 mutation, and this Ras superinduction is required to reach a threshold of ZEB1 sufficient for repression of miR-200 and tumor invasion.
- Subjects :
- Animals
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic pathology
Cellular Senescence genetics
Embryo, Mammalian metabolism
Embryo, Mammalian pathology
Fibroblasts metabolism
Fibroblasts pathology
Gene Expression Regulation, Neoplastic genetics
Homeodomain Proteins genetics
Kruppel-Like Transcription Factors genetics
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, Nude
MicroRNAs biosynthesis
MicroRNAs genetics
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasms genetics
Neoplasms pathology
RNA, Neoplasm biosynthesis
RNA, Neoplasm genetics
Retinoblastoma Protein genetics
Zinc Finger E-box-Binding Homeobox 1
ras Proteins genetics
Cell Transformation, Neoplastic metabolism
Homeodomain Proteins metabolism
Kruppel-Like Transcription Factors metabolism
Mutation
Neoplasms metabolism
Retinoblastoma Protein metabolism
ras Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 288
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23443660
- Full Text :
- https://doi.org/10.1074/jbc.M112.434951