Loss of p27Kip1 but not p21Cip1 decreases survival and synergizes with MYC in murine lymphomagenesis

AUTOR(ES)

Martins, Carla P.

FONTE

Oxford University Press

RESUMO

The cyclin-dependent kinase (CDK) inhibitors p21Cip1 and p27Kip1 are induced in response to anti-proliferative stimuli and block G1/S-phase progression through the inhibition of CDK2. Although the cyclin E–CDK2 pathway is often deregulated in tumors the relative contribution of p21Cip1 and p27Kip1 to tumorigenesis is still unclear. The MYC transcription factor is an important regulator of the G1/S transition and its expression is frequently altered in tumors. Previous reports suggested that p27Kip1 is a crucial G1 target of MYC. Our study shows that in mice, deficiency for p27Kip1 but not p21Cip1 results in decreased survival to retrovirally-induced lymphomagenesis. Importantly, in such p27Kip1 deficient lymphomas an increased frequency of Myc activation is observed. p27Kip1 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 p27Kip1 loss. We show that in lymphocytes, MYC overexpression and p27Kip1 deficiency independently stimulate CDK2 activity and augment the fraction of cells in S phase, in support of their distinct roles in tumorigenesis.

Documentos Relacionados

• p21Cip1 and p27Kip1 Regulate Cell Cycle Reentry after Hypoxic Stress but Are Not Necessary for Hypoxia-Induced Arrest
• p27Kip1 and p21Cip1 Are Not Required for the Formation of Active D Cyclin-cdk4 Complexes
• Analysis of Cyclin D3-cdk4 Complexes in Fibroblasts Expressing and Lacking p27kip1 and p21cip1
• Imuno-expressão dos genes supressores tumorais p53, p21WAF1/CIP1 e p27KIP1 em tumores astrocíticos humanos
• p21CIP1 and p57KIP2 control muscle differentiation at the myogenin step