The specific role of pRb in p16 INK4A-mediated arrest of normal and malignant human breast cells Journal Article
| Authors: | Bazarov, A. V.; Lee, W. J.; Bazarov, I.; Bosire, M.; Hines, W. C.; Stankovich, B.; Chicas, A.; Lowe, S. W.; Yaswen, P. |
| Article Title: | The specific role of pRb in p16 INK4A-mediated arrest of normal and malignant human breast cells |
| 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. © 2012 Landes Bioscience. |
| Keywords: | signal transduction; controlled study; protein expression; human cell; dna replication; protein function; protein localization; cell proliferation; protein analysis; cell structure; protein p16; breast cancer; cell growth; retinoblastoma; protein p53; breast epithelium; cell cycle arrest; senescence; retinoblastoma protein; cell cycle g1 phase; protein p107; protein p130; lifespan; growth rate; growth inhibition; p107; p130 |
| Journal Title: | Cell Cycle |
| Volume: | 11 |
| Issue: | 5 |
| ISSN: | 1538-4101 |
| Publisher: | Taylor & Francis Inc. |
| Date Published: | 2012-03-01 |
| Start Page: | 1008 |
| End Page: | 1013 |
| Language: | English |
| DOI: | 10.4161/cc.11.5.19492 |
| PROVIDER: | scopus |
| PUBMED: | 22333593 |
| PMCID: | PMC3323799 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 April 2012" - "Source: Scopus" |
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