In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 93, No. 26 ( 1996-12-24), p. 15215-15220
Abstract:
Cyclin E is an important regulator of cell cycle progression that
together with cyclin-dependent kinase (cdk) 2 is crucial for the G 1 /S transition during the mammalian cell cycle.
Previously, we showed that severe overexpression of cyclin E protein in tumor cells and tissues results in the appearance of lower molecular
weight isoforms of cyclin E, which together with cdk2 can form a kinase complex active throughout the cell cycle. In this study, we report that
one of the substrates of this constitutively active cyclin E/cdk2 complex is retinoblastoma susceptibility gene product (pRb) in
populations of breast cancer cells and tissues that also overexpress p16. In these tumor cells and tissues, we show that the expression of
p16 and pRb is not mutually exclusive. Overexpression of p16 in these cells results in sequestering of cdk4 and cdk6, rendering cyclin
D1/cdk complexes inactive. However, pRb appears to be phosphorylated throughout the cell cycle following an initial lag, revealing a time
course similar to phosphorylation of glutathione S -transferase retinoblastoma by cyclin E
immunoprecipitates prepared from these synchronized cells. Hence, cyclin E kinase complexes can function redundantly and replace the loss
of cyclin D-dependent kinase complexes that functionally inactivate pRb. In addition, the constitutively overexpressed cyclin E is also the
predominant cyclin found in p107/E2F complexes throughout the tumor, but not the normal, cell cycle. These observations suggest that
overexpression of cyclin E in tumor cells, which also overexpress p16, can bypass the cyclin D/cdk4-cdk6/p16/pRb feedback loop,
providing yet another mechanism by which tumors can gain a growth advantage.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.93.26.15215
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
1996
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink