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Loss of p27 Kip1 but not p21 Cip1 decreases survival and synergizes with MYC in murine lymphomagenesis
Author(s) -
Martins Carla P.,
Berns Anton
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf364
Subject(s) - biology , cyclin dependent kinase , cancer research , cyclin dependent kinase 2 , carcinogenesis , kinase , transgene , lymphoma , transcription factor , cyclin , cyclin e , cell cycle , microbiology and biotechnology , cancer , immunology , protein kinase a , gene , genetics
The cyclin‐dependent kinase (CDK) inhibitors p21 Cip1 and p27 Kip1 are induced in response to anti‐proliferative stimuli and block G 1 /S‐phase progression through the inhibition of CDK2. Although the cyclin E–CDK2 pathway is often deregulated in tumors the relative contribution of p21 Cip1 and p27 Kip1 to tumorigenesis is still unclear. The MYC transcription factor is an important regulator of the G 1 /S transition and its expression is frequently altered in tumors. Previous reports suggested that p27 Kip1 is a crucial G 1 target of MYC. Our study shows that in mice, deficiency for p27 Kip1 but not p21 Cip1 results in decreased survival to retrovirally‐induced lymphomagenesis. Importantly, in such p27 Kip1 deficient lymphomas an increased frequency of Myc activation is observed. p27 Kip1 deficiency was also shown to collaborate with MYC overexpression in transgenic lymphoma models. Thus, in vivo , the capacity of MYC to promote tumor growth is fully retained and even enhanced upon p27 Kip1 loss. We show that in lymphocytes, MYC overexpression and p27 Kip1 deficiency independently stimulate CDK2 activity and augment the fraction of cells in S phase, in support of their distinct roles in tumorigenesis.