J. Lukas et al., ONCOGENIC ABERRATIONS OF PL6(INK4 CDKN2) AND CYCLIN D1 COOPERATE TO DEREGULATE G(1) CONTROL/, Cancer research, 55(21), 1995, pp. 4818-4823
The p16(INK4/CDKN2), D-type cyclins, their partner cyclin-dependent ki
nases, and retinoblastoma protein constitute a G(1) regulatory pathway
commonly targeted in oncogenesis. We show that, unexpectedly, abnorma
lities of p16(INK4/CDKN2) occur concomitantly in two-thirds of cancer
cell lines harboring aberrations of cyclin D1. Gene and protein transf
er experiments demonstrated that concurrent alterations of cyclin D1 a
nd p16 levels cooperate to (de)regulate G(1) control in diploid fibrob
lasts, and that both events influence growth of retinoblastoma (RB)-po
sitive, but not RB-deficient cancer cells. These results show that bio
logical consequences of deregulating individual components along the p
athway are unequal, reflecting their hierarchical roles in the G(1) ch
eckpoint control. Whereas RB defects eliminate the checkpoint complete
ly, aberrations of the upstream components, such as cyclin D1 and p16(
INK4/CDKN2), can cooperate in multistep tumorigenesis.