Bazarov, A. V., Jae Lee, W., Bazarov, I., Bosire, M., Hines, W. C., Stankovich, B., Chicas, A., Lowe, S. W., Yaswen, P. (March 2012) The specific role of pRb in p16(INK4A)-mediated arrest of normal and malignant human breast cell. Cell Cycle, 11 (5). ISSN 1551-4005 (Electronic)1551-4005 (Linking)
Abstract
RB family proteins pRb, p107 and p130 have similar structures and overlapping functions, enabling cell cycle arrest and cellular senescence. pRb, but not p107 or p130, is frequently mutated in human malignancies. In human fibroblasts acutely exposed to oncogenic ras, pRb has a specific role in suppressing DNA replication, and p107 or p130 cannot compensate for the loss of this function; however, a second p53/p21-dependent checkpoint prevents escape from growth arrest. This model of oncogene-induced senescence requires the additional loss of p53/p21 to explain selection for preferential loss of pRb function in human malignancies. We asked whether similar rules apply to the role of pRb in growth arrest of human epithelial cells, the source of most cancers. In two malignant human breast cancer cell lines, we found that individual RB family proteins were sufficient for the establishment of p16-initiated senescence, and that growth arrest in G 1 was not dependent on the presence of functional pRb or p53. However, senescence induction by endogenous p16 was delayed in primary normal human mammary epithelial cells with reduced pRb but not with reduced p107 or p130. Thus, under these circumstances, despite the presence of functional p53, p107 and p130 were unable to completely compensate for pRb in mediating senescence induction. We propose that early inactivation of pRb in pre-malignant breast cells can, by itself, extend proliferative lifespan, allowing acquisition of additional changes necessary for malignant transformation.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA replication diseases & disorders > cancer > cancer types > breast cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Shared Resources > DNA Sequencing Service CSHL labs > Lowe lab CSHL Cancer Center Program > Cancer Genetics |
| Depositing User: | Matt Covey |
| Date: | 1 March 2012 |
| Date Deposited: | 26 Dec 2014 19:21 |
| Last Modified: | 13 Oct 2015 19:28 |
| PMCID: | PMC3323799 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30993 |
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