S-phase kinase-associated protein 2 expression in non-Hodgkin's lymphoma inversely correlates with p27 expression and defines cells in S phase.
The protein expression of the cyclin-dependent kinase inhibitor p27 is often deregulated in human tumors. In lymphomas the inactivation of p27 is achieved through either increased degradation(1) or sequestration via D cyclins,(2) and p27 protein levels have been shown to have a prognostic significance.(1,3) Recently, S-phase kinase-associated protein 2 (Skp2) has been proved to mediate p27 degradation in normal cells(4-7) and to have oncogenetic properties.(8,9) In this study, B-, T-, and myeloid hematopoietic cell lines and a well-characterized panel of human lymphomas (n = 244) were studied for the expression of Skp2. In human lymphomas, the expression of Skp2 strongly related to the grade of malignancy, being low in indolent tumors and very high in aggressive lymphomas. Moreover, the percentages of Skp2- and S-phase-positive cells, as measured by DNA content or BrdU labeling, strictly matched and closely parallel that of Ki-67 and cyclin A. An inverse correlation between Skp2 and p27 was found in the majority of lymphoma subtypes. Nonetheless, most mantle cell lymphomas and a subset of diffuse large cell lymphomas failed to show this correlation, suggesting that alternative pathway(s) for the regulation of p27 might exist. The detection of Skp2 protein either by flow cytometry or by immunohistochemistry represents a simple method to precisely assess the S phase of lymphomas. The potential diagnostic and prognostic value of Skp2 is discussed.
Chiarle
Roberto
R
Department of Pathology and Kaplan Comprehensive CancerCenter, New York University School of Medicine, New York,New York.
Fan
Yan
Y
Piva
Roberto
R
Boggino
Hugo
H
Skolnik
Jeffrey
J
Novero
Domenico
D
Palestro
Giorgio
G
De Wolf-Peeters
Chris
C
Chilosi
Marco
M
Pagano
Michele
M
Inghirami
Giorgio
G
D015415:Biomarkers; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006801:Humans; D008221:Lymphoid Tissue / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism* / Q000473:pathology*; D016196:S Phase / Q000502:physiology*; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D015415:Biomarkers; D018797:Cell Cycle Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27