Differential patterns of cell cycle regulatory proteins expression in transgenic models of thyroid tumours.
Cell cycle proteins regulate the transitions from G1 to S and G2 to M phases. In higher eukaryotes, their function is controlled by intracellular cascades regulated by extracellular growth factors. We have studied in previously described transgenic mouse models for thyroid proliferative diseases the expression of the key proteins regulating the cell cycle by Western blotting and immunohistochemistry, and have correlated the observations with the known actions of the transgenes on the signal transduction cascades. In the adenosine A2a receptor model, the cyclic AMP pathway, upstream of the Rb family cell division block, is constitutively activated. In the model expressing HPV 16 E7 protein, the Rb-like proteins are inhibited. Cyclin-dependent kinases cdk4, cdk2 and cdc2, and the associated cyclins D, E and A have been studied. Cyclin D3 appears as the major cyclin D subtype expressed in mouse thyroid epithelial cells in normal and transgenic mice. In the adenosine A2aR model, all cell cycle proteins tested were accumulated. In the E7 model, all cell cycle proteins except for D-type cyclins and cdk4 were also accumulated. A similar pattern was observed in thyroids coexpressing both transgenes, suggesting a dominant effect of E7 over the consequences of the cAMP cascade activation. The cyclin-dependent kinase inhibitors p21cip1/waf1 and p27kip1 were not downregulated in these proliferating thyroids which suggest other roles than the inhibition of the cell cycle progression.
Coppée
F
F
IRIBHN, Université Libre de Bruxelles, Campus Erasme, Belgium.
Depoortere
F
F
Bartek
J
J
Ledent
C
C
Parmentier
M
M
Dumont
J E
JE
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D019925:Cyclin A / Q000378:metabolism; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D013954:Thyroglobulin / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056741:Cyclin D; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D025521:Tumor Suppressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013954:Thyroglobulin; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases