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. 2001 Mar;54(3):229–235. doi: 10.1136/jcp.54.3.229

Expression of cyclins and cyclin dependent kinases in human benign and malignant melanocytic lesions*

J Georgieva 1, P Sinha 1, D Schadendorf 1
PMCID: PMC1731381  PMID: 11253137

Abstract

Aims—The regulation of cell proliferation is a key event in normal development, pathophysiological responses to injury, and tumorigenesis. The orderly progression of cells through the cell cycle depends on a finely tuned balance between the concentrations of activated cyclins and cyclin dependent kinases. This study was undertaken to compare the expression of cell cycle regulators in benign and malignant melanocytic lesions during tumour progression.

Methods—Immunohistochemistry was used to analyse 49 primary cutaneous malignant melanomas, 18 metastatic melanomas, and 12 histologically confirmed naevus cell naevi for their expression of cyclins (A, B1, D1, D2, D3, and E) and cyclin dependent kinases (CDK1, CDK2, and CDK4).

Results—Cyclin E and CDK2 had the highest expression patterns in human cutaneous melanomas and metastases and correlated positively with histological type and tumour stage. Cyclins B1, D2, and D3 had significantly increased expression in metastases, but normal or even decreased expression in primary melanomas. However, cyclins A and D1, and CDK1 and CDK4 were expressed very weakly in situ with no significant differences between naevi, melanomas, or metastases, and there was no correlation with histopathological staging. The specificity of recognition by the antibodies used was confirmed by western blotting on a panel of seven human melanoma cell lines. Cyclins A, B, and E were expressed by all seven, whereas cyclin D1 was detectable in six of seven and CDK2 and cdc2 were present in five of seven lines analysed.

Conclusions—Taken together, this study demonstrated a significant increase of cyclin E and CDK2 expression during tumour progression in malignant melanomas.

Key Words: melanoma • immunohistology • naevus • cyclin E • cyclin dependent kinase 2 • cyclin B1

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Figure 1 Simplified scheme of the different phases of the cell cycle and their components. Not shown in the scheme are the inhibitors of the cyclin–CDK complexes (p15, p16, p18, p21, and p27) and other cyclin activating kinases and phosphatases.

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Figure 2 Western blot analysis using monoclonal antibodies listed in table 2. Seven human melanoma lines were analysed: 1, SK-Mel-23; 2, WM 98–1; 3, UKRV-Mel 4; 5, SK-Mel-37; 6, UKRV-Mel-2; and 7, MV3.

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Figure 3 Immunohistological staining of tissue sections using the alkaline phosphatase antialkaline phosphatase (APAAP) technique. (A) A primary melanoma stained with an anticyclin B1 antibody (magnification, x20) and (B) a metastasis stained with anticyclin D3 (magnification, x80). (C) Immunohistological staining of a primary melanoma with an anticyclin E (magnification, x20) and (D) with an anti-CDK2 monoclonal antibody (magnification, x40)

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Figure 4 Correlation of cyclin E expression with (A) CDK2, (B) cyclin D3, and (C) cyclin B1.

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