p57KIP2 expression and loss of heterozygosity during immortal conversion of cultured human mammary epithelial cells - PubMed (original) (raw)

. 1999 Oct 15;59(20):5112-8.

Affiliations

PMID: 10537284

p57KIP2 expression and loss of heterozygosity during immortal conversion of cultured human mammary epithelial cells

T Nijjar et al. Cancer Res. 1999.

Abstract

We have uncovered a novel role for the cyclin-dependent kinase inhibitor, p57KIP2, during the immortalization of cultured human mammary epithelial cells (HMECs). HMECs immortalized after chemical carcinogen exposure initially expressed little or no telomerase activity, and their telomeres continued to shorten with passage. Cell populations whose mean terminal restriction fragment (TRF) length declined to < or = 3 kb exhibited slow heterogeneous growth and contained many nonproliferative cells. These conditionally immortal HMEC cultures accumulated large quantities of p57 protein. With continued passage, the conditionally immortal cell populations very gradually converted to a fully immortal phenotype of good uniform growth, expression of high levels of telomerase activity, and stabilization of telomere length. The fully immortal HMECs that grew well did not accumulate p57 in G0 or during the cell cycle. DNA and RNA analysis of mass populations and individual subclones of conditionally immortal HMEC line 184A1 showed that continued growth of conditionally immortal cells with critically short telomeres was repeatedly accompanied by loss of the expressed p57 allele and transient expression of the allele imprinted previously. Conditionally immortal 184A1 with mean TRF > 3 kb, infected with retroviruses containing the p57 gene, exhibited premature slow heterogeneous growth. Conversely, exogenous expression of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, in 184A1 with mean TRF > 3 kb prevented both the slow heterogeneous growth phase and accumulation of p57 in cycling populations. These data indicate that in HMECs that have overcome replicative senescence, p57 may provide an additional barrier against indefinite proliferation. Overcoming p57-mediated growth inhibition in these cells may be crucial for acquisition of the unlimited growth potential thought to be critical for malignant progression.

PubMed Disclaimer

Cited by

Epigenetic changes accompanying human mammary epithelial cell immortalization.
Yaswen P, Stampfer MR. Yaswen P, et al. J Mammary Gland Biol Neoplasia. 2001 Apr;6(2):223-34. doi: 10.1023/a:1011364925259. J Mammary Gland Biol Neoplasia. 2001. PMID: 11501582 Review.
Expression of p57(KIP2) potently blocks the growth of human astrocytomas and induces cell senescence.
Tsugu A, Sakai K, Dirks PB, Jung S, Weksberg R, Fei YL, Mondal S, Ivanchuk S, Ackerley C, Hamel PA, Rutka JT. Tsugu A, et al. Am J Pathol. 2000 Sep;157(3):919-32. doi: 10.1016/S0002-9440(10)64605-6. Am J Pathol. 2000. PMID: 10980131 Free PMC article.
Does cyclin E and p57kıp2 expression have prognostic and survival value in colorectal adenocarcinoma?
Ozgur T, Sumbul AT, Yaldız M, Temiz M, Akdağ A. Ozgur T, et al. Int J Clin Exp Pathol. 2018 Aug 1;11(8):3867-3875. eCollection 2018. Int J Clin Exp Pathol. 2018. PMID: 31949774 Free PMC article.
Tumor suppression by p53: making cells senescent.
Qian Y, Chen X. Qian Y, et al. Histol Histopathol. 2010 Apr;25(4):515-26. doi: 10.14670/HH-25.515. Histol Histopathol. 2010. PMID: 20183804 Free PMC article. Review.
The polycomb group protein BMI1 is a transcriptional target of HDAC inhibitors.
Bommi PV, Dimri M, Sahasrabuddhe AA, Khandekar J, Dimri GP. Bommi PV, et al. Cell Cycle. 2010 Jul 1;9(13):2663-73. doi: 10.4161/cc.9.13.12147. Cell Cycle. 2010. PMID: 20543557 Free PMC article.

p57KIP2 expression and loss of heterozygosity during immortal conversion of cultured human mammary epithelial cells - PubMed (original) (raw)