Differential patterns of cell cycle regulatory proteins expression in transgenic models of thyroid tumours

Abstract

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 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, 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 A 2a R 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 e ect of E7 over the consequences of the cAMP cascade activation. The cyclin-dependent kinase inhibitors p21 cip1/waf1 and p27 kip1 were not downregulated in these proliferating thyroids which suggest other roles than the inhibition of the cell cycle progression.

Evidence for a Telomere-Independent “Clock” Limiting RAS Oncogene-Driven Proliferation of Human Thyroid Epithelial Cells

“…p27 is expressed at high levels in normal thyrocytes both in vitro (this study) and in the intact thyroid gland, in both human (17,40,60) and mouse (13). Many studies suggest that p27 plays a role in growth arrest accompanying differentiation (16,49,72), and p27-null mice exhibit hyperplasia of many highly differentiated cell populations, including endocrine glands (19,33,47) (although thyroid was not specifically studied).…”

Cyclin D3 accumulation and activity integrate and rank the comitogenic pathways of thyrotropin and insulin in thyrocytes in primary culture

“…We have shown that cyclin D3 is the predominant cyclin D expressed in quiescent thyrocytes of primary cultures of dog tissue , and of mice in vivo (Coppee et al, 1998). In dog thyrocytes, TSH (cAMP), unlike all the other known mitogenic factors, does not induce the accumulation of cyclins D , but stimulates the expression of p27 kip1 (Depoortere et al, 1996).…”

Genetic Alterations in Thyroid Cancer: The Role of Mouse Models

“…14,15,48 Coexpression of both transgenes enhanced tumorigenesis. In a mouse model of Carney complex tumor syndrome, a disease involving multiple endocrine and non-endocrine neoplasms, heterozygous knockout of the R1A regulatory subunit of protein kinase A led to papillary thyroid carcinoma development in 5 out of 44 mice.…”