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Int J Biochem Cell Biol. 2002 Nov;34(11):1382-94.

Molecular changes accompanying senescence and immortalization of cultured human mammary epithelial cells.

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1
Department of Cell and Molecular Biology, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 70A-1118, Berkeley, CA 94720, USA. p_yaswen@lbl.gov

Abstract

Limits on the proliferative potential of cultured normal human cells may be consequences of pathways that exist to suppress tumorigenicity. Human mammary epithelial cells (HMEC) employ several mechanisms to prevent unlimited growth. One mechanism may be activated by stress, and is associated with upregulated expression of p16(INK4a). In serum-free medium, some HMEC arise spontaneously which do not express p16. These "post-selection" HMEC are capable of long-term proliferation, but ultimately cease growth when their telomeres become very short. As they approach a growth plateau, termed agonescence, post-selection HMEC populations accumulate chromosome abnormalities. In contrast to the crisis exhibited by cells lacking functional p53, agonescent cells can be maintained as viable cultures. Although transduction of hTERT, the catalytic subunit of telomerase, into post-selection cells can, by itself, efficiently produce immortality and avoid agonescence, the errors that produce telomerase reactivation during carcinogenesis are not known. The block to endogenous telomerase reactivation in HMEC is extremely stringent. However, if one predisposing error is present, the probability greatly increases that additional error(s) required for immortalization may be generated by genomic instability encountered during agonescence. In p53(+) HMEC immortalized after chemical carcinogen exposure, the events involved in overcoming agonescence can be temporally separated from activation of telomerase. We have used the term "conversion" to describe the gradual process that leads to telomerase activation, telomere length stabilization, decreased p57 (KIP2) expression, and increased ability to grow uniformly well in the presence or absence of TGF beta. In the presence of active p53, conversion may represent a rate-limiting step in immortal transformation.

PMID:
12200033
[Indexed for MEDLINE]

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