Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies.
The Polo-like kinases (Plks) are a highly conserved family of protein kinases that function in regulation of cell cycle and DNA damage-induced checkpoints. Evidence of a tumor suppressor function for the Plks in human neoplasia is lacking. Here, we report that Snk/Plk2 is transcriptionally down-regulated in B-cell neoplasms. Silencing occurs with very high frequency in Burkitt lymphoma (BL) but is also detected in B-cell neoplasms of other types and is associated with aberrant cytosine methylation in the CpG island located at the 5' end of the SNK/PLK2 gene. Silencing is specific to malignant B cells because SNK/PLK2 was unmethylated (and expressed) in primary B lymphocytes, in EBV-immortalized B lymphoblastoid cell lines (LCLs), and in adenocarcinomas (of the breast) and squamous-cell carcinomas (of the head and neck). Expression of Snk/Plk2 in BL cell lines was restored by demethylating agents. The related PLK1 and PLK3 (FNK/PRK) genes were overexpressed in BL cell lines lacking Snk/Plk2 expression, consistent with functional degeneracy among the Plk family. Ectopic expression of Snk/Plk2 in BL cells resulted in apoptosis, a potential mechanistic basis underlying the strong selective pressure for abrogation of Snk/Plk2 function in B-cell neoplasia.
Syed
Nelofer
N
Breakthrough Breast Cancer Centre, Institute of Cancer Research, Fulham Rd, London SW3 6JB, United Kingdom.
Smith
Paul
P
Sullivan
Alexandra
A
Spender
Lindsay C
LC
Dyer
Martin
M
Karran
Lorraine
L
O'Nions
Jenny
J
Allday
Martin
M
Hoffmann
Ingrid
I
Crawford
Dorothy
D
Griffin
Beverley
B
Farrell
Paul J
PJ
Crook
Tim
T
D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes; D018797:Cell Cycle Proteins / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D015448:Leukemia, B-Cell / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; D000097868:Polo-like Kinases
D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; C486256:PLK3 protein, human; D000097868:Polo-like Kinases; C496126:PLK2 protein, human