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Overexpression of cyclin D1 inhibits TNF‐induced growth arrest
Author(s) -
Moneo Victoria,
Guijarro Maria del Valle,
Link Wolfgang,
Carnero Amancio
Publication year - 2003
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10529
Subject(s) - tumor necrosis factor alpha , cyclin d1 , microbiology and biotechnology , cyclin dependent kinase , chemistry , cancer research , cancer cell , cytokine , biology , apoptosis , cell cycle , biochemistry , cancer , immunology , genetics
Although activated macrophages destroy cancer cells more effectively than normal cells, the facility to escape activated macrophages is a characteristic of tumor cells. One of the mechanisms responsible for the specific killing of tumor cells by macrophages is the production of the cytokine tumor necrosis factor alpha (TNF). Therefore, resistance to TNF may provide such cancer cells a selective advantage against host elimination. In the present work we explore the possibility that cyclin D1 overrides the cytostatic effect of TNF. We show that TNF induces p21 waf1 protein in malignant melanoma A375 cells and its binding to CDK2/4 and 6 proteins, and thereby inhibiting the activity of these complexes. This inhibition leads the cells to a G1 arrest. Overexpression of cyclin D1 in these cells makes them insensitive to TNF treatment with the recovery of CDK activity, however, is unable to overcome the inhibitory action of etoposide blocking the cells on G2/M. The bypass of TNF‐induced G1 arrest seems to be related to the increase in the stability of cyclin D bound CDK complexes, increasing the total amount of CDK2/4 and 6 complexes and leading to a functional down titration of the p21 waf1 molecules. In these conditions the TNF‐induced increase of p21 waf1 is not sufficient to inhibit the high amount of cyclin D‐bound complexes. This hypothesis is supported by the fact that a reduction in the levels of p21 waf1 protein, induced by the expression of a mRNA antisense against p21 waf1 , is also able to bypass of TNF‐induced arrest. Our results confirm that p21 waf1 has an essential role in TNF‐induced arrest and that the deregulation of cyclin D1 may be one of the mechanisms to escape physiological signals to restrict tumoral growth. © 2003 Wiley‐Liss, Inc.