Antiproliferative function of p27(kip1) is frequently inhibited in highly malignant Burkitt's lymphoma cells

Lack of detectable expression of p27(kip1) cyclin dependent kinase inhibito r has previously been correlated with high degree of malignancy in human br east, colorectal, gastric and smalt cell lung carcinomas. Here me demonstra te that an inverse correlation between p27(kip1) expression and tumour mali gnancy also exists in most types of human B cell lymphomas examined. A clea r exception was Burkitt's lymphoma (BL), a highly malignant tumour which of ten expresses high levels of p27(kip1). Analysis of p27(kip1) derived from Burkitt's lymphoma cell lines expressing high levels of p27(kip1), BL40 and BL41, in a cyclin E/cdk2 kinase inhibition assay demonstrated that p27(kip 1) is not permanently inactivated since heat treatment can restore the inhi bitory activity of p27(kip1). However, p27(kip1) expressed in these two cel l lines is largely sequestered in inactive complexes and me have no evidenc e that c-myc or Epstein-Barr virus are responsible for the sequestration of p27(kip1) in these two cell lines although c-myc and EBV are two oncogenic agents often associated with Burkitt's lymphomas. Interestingly, we observ ed that high level p27(kip1) expression often correlated,vith cyclin D3 ove rexpression both in vivo and in BL cell lines. The majority of p27(kip1) in BL40 cells was complexed with cyclin D3 indicating that overexpressed cycl in D3 may at least be part of the sequestering activity for the inhibitory function of p27(kip1). Furthermore, cyclinD3/cdk4 complex could sequester p 27(kip1) in a cyclin E/cdk2 kinase assay in vitro. Finally, me show that cy clin D3 transfected into an inducible p27(kip1) cell line could overcome th e G1 arrest mediated by p27(kip1). These results argue that in addition to down-regulation of p27(kip1) expression, some tumour cells can sequester an d tolerate the antiproliferative function of p27(kip1), They also suggest a novel role for the overexpression of D-type cyclins as one pathway allowin g tumour cells to overcome the antiproliferative function of p27(kip1).