Deregulated expression of cell-cycle proteins during premalignant progression in SENCAR mouse skin

Abstract

It is now evident that several genes encoding regulatory activities that control the mammalian cell cycle, particularly some that control the progression of quiescent cells through G1 and into S phase, are targets for alterations that underlie the development of neoplasms. Here, we made a sequential study of alterations in cell cycle protein expression and complex formation among cyclin, cyclin dependent kinases (CDKs) and CDK inhibitors (CKIs) during premalignant progression in SENCAR mouse skin tumors. Changes in the level of expression were observed in positive (cyclin D1, D2, and E2F family members) and negative regulators (p16 Ink4a , p57 Kip2 ) of the cell cycle. Also, we observed the formation of cyclin/CDK/CKI complexes. The amounts of these proteins and complexes increased substantially at speci®c times during promotion but not during malignant conversion to carcinomas. These data show that deregulation of growth control occurs in benign tumors and that subsequent mutations not involved cell-cycle regulation are probably necessary to induce invasive behavior.

Cyclin D2 and cyclin D3 play opposite roles in mouse skin carcinogenesis

“…We previously observed that cyclin D2 and cyclin D1 are aberrantly expressed in mouse skin papillomas (Rodriguez-Puebla et al, 1998a), suggesting that these cyclins play an important role in tumor development. Thus, we asked whether the reduction of cyclin D2 levels is in part responsible for the diminished tumorigenesis observed in K5-D3 mice.…”

“…In the last few years, we and others have used the mouse skin model to study the role of D-type cyclins in normal and neoplastic proliferation (Zhang et al, 1997;Rodriguez-Puebla et al, 1998aMiliani de Marval et al, 2004). These studies showed that cyclin D1 and D2 are overexpressed in mouse skin papillomas and squamous cell carcinomas (SCC), whereas cyclin D3 protein levels remain constant in normal epidermis and skin tumors (Rodriguez-Puebla et al, 1998b).…”

Cyclin D2 Overexpression in Transgenic Mice Induces Thymic and Epidermal Hyperplasia whereas Cyclin D3 Expression Results Only in Epidermal Hyperplasia

“…[35][36][37] The three D-type cyclins are differentially expressed in normal mouse epidermis,. 27,29 Cyclin D1 protein expression and cyclinD1-CDK4/6 complex formation are strongly regulated during the G 1 phase after 12-0-tetradecanoylphorbol-13-acetate (TPA) stimulation of keratinocytes. 29 On the other hand, cyclin D2 and cyclin D3 protein expression seem to be constitutive and only minor changes in their protein levels were observed after TPA stimulation.…”

“…29 Another interesting difference is that during premalignant tumor progression in chemically-induced mouse carcinogenesis, cyclin D1 and cyclin D2 are overexpressed and form complexes with CDK4/6, whereas cyclin D3 only forms complexes with CDK4/6 in hyperproliferative epidermis (hyperplastic skin). 27 We have previously reported the generation of a transgenic mouse that expresses human cyclin D1 in squamous epithelial tissues, resulting in moderate epidermal and severe thymic hyperplasia. 30,31 To complete the study of the role of D-type cyclins in squamous epithelial tissues, we generated transgenic mice that expressed either cyclin D2 or cyclin D3, driven by the regulatory sequence of bovine keratin 5 (K5D2 and K5D3).…”

“…26 The use of this model allowed us to detect expression of the three D-type cyclins in normal, hyperplastic and neoplastic epidermis in vivo. 27,28 Cyclin D1 and cyclin D2 are expressed at the mid-G 1 phase and form complexes with CDK4/6, a process that is dependent on the relative abundance of these cyclins. Cyclin D3 also forms complexes with CDK4/6; however, complex formation requires an additional regulatory event other than the simple relative abundance of these proteins.…”