The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis
Open accessAbstract
Autophagy is a conserved cellular process for bulk degradation of intracellular protein and organelles in lysosomes. In contrast to elegant studies of beclin1 using mouse models and cultured cells demonstrating a tumor suppression function for autophagy, knockout of other essential autophagy proteins such as ATG5, ATG7, or FIP200 (FAK family-interacting protein of 200 kDa) in various tissues did not lead to malignant tumor development in vivo. Here, we report that inhibition of autophagy by FIP200 ablation suppresses mammary tumor initiation and progression in a mouse model of breast cancer driven by the PyMT oncogene. Deletion of FIP200 resulted in multiple autophagy defects including accumulation of ubiquitinated protein aggregates and p62/SQSTM1, deficient LC3 conversion, and increased number of mitochondria with abnormal morphology in tumor cells. FIP200 deletion did not affect apoptosis of mammary tumor cells or Ras-transformed mouse embryonic fibroblasts (MEFs), but significantly reduced their proliferation in both systems. We also observed a reduced glycolysis and cyclin D1 expression in FIP200-null mammary tumor cells and transformed MEFs. In addition, gene profiling studies revealed significantly elevated expression of interferon (IFN)-responsive genes in the early tumors of FIP200 conditional knockout mice, which was accompanied by increased infiltration of effector T cells in the tumor microenvironment triggered by an increased production of chemokines including CXCL10 in FIP200-null tumor cells. Together, these data provide strong evidence for a protumorigenesis role of autophagy in oncogene-induced tumors in vivo and suggest FIP200 as a potential target for cancer therapy.
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Metadata
- Authors
- Wei, H., Wei, S., Gan, B., Peng, X., Zou, W., & Guan, J.-L.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-07-15
- Volume
- 25
- Issue
- 14
- Pages
- 1510-1527
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2140612465
- Cited by
- 401
- References
- 28
- Type
- posted content
- Language
- en
- Open access
- diamond
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- Wei, H., Wei, S., Gan, B., Peng, X., Zou, W., & Guan, J.-L. (2011). Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes & Development. https://doi.org/10.1101/gad.2051011
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