Alterations of the p27KIP1 gene in non-Hodgkin's lymphomas and adult T- cell leukemia/lymphoma

Abstract

The protein p27KIP1 belongs to a recently identified family of proteins termed cyclin-dependent kinase inhibitors (CDKIs). These proteins play an important role in regulating cell-cycle progression and loss of their function has been implicated in tumorigenesis. Transforming growth factor beta (TGF-beta) may induce cell growth arrest through p27 activation. TGF-beta often loses its ability to arrest growth of transformed cells; this could potentially occur through a defect in p27. To determine the role of p27 in tumorigenesis, we examined its mutational status in 74 non-Hodgkin's lymphomas (NHLs) (52 of B-cell phenotype, 22 of T-cell phenotype), 5 lymphoma cell lines, and 42 adult T-cell leukemias/lymphomas (ATLs) using polymerase chain reaction- single strand conformational polymorphism (PCR-SSCP) and Southern blot analyses. A nonsense mutation (stop codon) that could result in expression of a truncated nonfunctional p27 protein was detected at codon 76 in one case of acute lymphomatous ATL, but not in matched normal tissues. Previously undescribed polymorphisms were also identified at codon 109 in the lymphomas and at codon 55 in the ATLs. Two homozygous deletions of the p27 gene were detected in one case of B- immunoblastic NHL and in one case of acute ATL by Southern blot hybridization. These results indicate that p27 gene alterations are rare events in NHLs and ATLs, but may play an important role in the pathogenesis of some hematologic malignancies.

Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc.

“…Whether the p27 gene is a tumour suppressor is still unclear. p27 mutations occur very infrequently and in few human tumours Morosetti et al, 1995;Pietenpol et al, 1995;Ponce-Castaneda et al, 1995;Harper and Elledge, 1996). p27 deletion in mice increases cell proliferation and body size, but not the incidence of multiple tumours.…”

Degradation of p27Kip cdk inhibitor triggered by Kaposi's sarcoma virus cyclin-cdk6 complex

“…Loss of INK inhibitors through mutation or transcriptional silencing is a frequent event during tumourigenesis (reviewed in Palmero and Peters, 1996;Carnero and Hannon, 1998). Although described, mutations in the CIP/ KIP-type inhibitors are rarely seen (Morosetti et al, 1995;Shi et al, 1996;Spirin et al, 1996). However, p21 Cip induction is affected by mutations in the tumour suppressor p53.…”

Growth regulation by p27Kip1 is abrogated by multiple mechanisms in aggressive malignant lymphomas

“…In lymphoid cells, the level of p27 Kip1 mRNA and protein is high in non‐proliferating lymphocytes and transforming growth factor‐β (TGF‐β)‐treated lymphocytes (Kamesaki et al , 1998), whereas in activated and proliferating cells such as centroblasts, immunoblasts or mitogenically stimulated peripheral blood lymphocytes (Solvason et al , 1996), the level of p27 Kip1 expression is low (Vrhovac et al , 1998). p27 Kip1 gene alterations are either rare (Morosetti et al , 1995) or absent (Quintanilla‐Martinez et al , 1998) in lymphoid neoplasms, thus epigenetic mechanisms occurring at the transcriptional, translational or post‐translational level are important in p27 Kip1 deregulation (Hengst & Reed, 1996). The ubiquitin proteolysis pathway is a critical mode of regulating p27 Kip1 levels (Pagano et al , 1995) with increased steady state levels and stability seen in quiescent cells (Hengst & Reed, 1996; Sandhu et al , 1997).…”