The low molecular weight cyclin E isoforms augment angiogenesis and metastasis of human melanoma cells in vivo.
Immunohistochemical analysis has consistently shown that cyclin E is up-regulated in human malignant melanomas in vivo. Here we analyzed such expression in more detail and show that cyclin E is overexpressed and present in low molecular weight (LMW) isoforms in metastatic melanoma and in a subset of primary invasive melanoma tumor tissues, but not in benign nevi. Human metastatic melanoma cell lines, but not normal melanocytes, also expressed the LMW cyclin E forms. The biological significance of these findings was established by showing that overexpression of two LMW cyclin E forms named cyclin E truncated 1 [cyclinE(T1)] and cyclin E truncated 2 [cyclinE(T2)] in a low tumorigenic and non-metastatic primary cutaneous melanoma cell line generated angiogenic tumors with prominent perineural invasion compared with full-length cyclin E. In addition, cyclin E(T1)- and cyclin E(T2)-expressing melanoma cells displayed a dramatic increase in the incidence and number of metastases in an experimental lung metastasis assay. Together, these results indicate that the LMW cyclin E forms are functional and likely act as regulators of human melanoma tumor progression and invasion.
Bales
Elise
E
Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Mills
Lisa
L
Milam
Nancy
N
McGahren-Murray
Mollianne
M
Bandyopadhyay
Debdutta
D
Chen
Dahu
D
Reed
Jon A
JA
Timchenko
Nikolai
N
van den Oord
Joost J
JJ
Bar-Eli
Menashe
M
Keyomarsi
Khandan
K
Medrano
Estela E
EE
D000818:Animals; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D019927:Cyclin E / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006801:Humans; D008297:Male; D008545:Melanoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008970:Molecular Weight; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D020033:Protein Isoforms; D014162:Transfection; D014183:Transplantation, Heterologous
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020033:Protein Isoforms; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2