Journal
ONCOGENE
Volume 21, Issue 41, Pages 6328-6339Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1205780
Keywords
conversion; senescence; immortalizatiom; Raf-1; p16(INK4a); human mammary epithelial cells
Funding
- NCI NIH HHS [CA-24822] Funding Source: Medline
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Using an estrogen-inducible retroviral system, we demonstrate that oncogenie Raf-1 induces growth arrest and morphological changes in finite lifespan human mammary epithelia] cells (HMEC). This arrest does not rely on expression of the cyclin-dependent kinase inhibitor (CKI) p16(INK4a), nor on changes in expression of the CKIs p21(Cip1), p14(ARF), p27(Kip1) or p57(Kip2). The Raf-induced arrest is independent of viral oncogene mediated inactivation of p53 and pRB, or e-myc overexpression. Flow cytometric analysis demonstrates that cells arrest in both G1 and G2. The Raf-induced arrest is mitigated or eliminated in some immortally transformed HMEC. Immortal HMEC that have both overcome replicative senescence and undergone the recently described conversion process maintain growth in the presence of transduced oncogenic Raf-1; they also gain EGF-independent growth and a low frequency of anchorage-independent growth. However, HMEC that have overcome replicative senescence but have not undergone conversion and HMEC immortalized by transduction with the catalytic subunit of telomerase, hTERT, remain severely growth arrested. These results indicate that the molecular mechanisms responsible for the Raf-1-induced growth arrest may Nary among different finite lifespan cell types, and that in HMEC, this mechanism is altered during the conversion process, rather than as a direct consequence of overcoming senescence or expressing hTERT.
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