DIFFERENTIAL PATTERNS OF CELL-CYCLE REGULATORY PROTEINS EXPRESSION INTRANSGENIC MODELS OF THYROID-TUMORS

Cell cycle proteins regulate the transitions from G1 to S and G2 to M phases. In higher eukaryotes, their function is controlled by intracel lular cascades regulated by extracellular growth factors, We have stud ied m previously described transgenic mouse models for thyroid prolife rative diseases the expression of the key proteins regulating the cell cycle by Western blotting and immunohistochemistry, and have correlat ed the observations with the known actions of the transgenes on the si gnal transduction cascades. In the adenosine A(2a) 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, cdk 2 and cdc2, and the associated cyclins D, E and A have been studied. C yclin D3 appears as the major cyclin D subtype expressed in mouse thyr oid epithelial cells in normal and transgenic mice. In the adenosine A (2a)R model, all cell cycle proteins tested were accumulated. In the E 7 model, all cell cycle proteins except for D-type cyclins and cdk4 we re also accumulated. A similar pattern was observed in thyroids coexpr essing both transgenes, suggesting a dominant effect of E7 over the co nsequences of the cAMP cascade activation. The cyclin-dependent kinase inhibitors p21(cip1/waf1) and pt27(kip1) were not downregulated in th ese proliferating thyroids which suggest other roles than the inhibiti on of the cell cycle progression.