Aberrant cell cycle progression contributes to the early-stage accelerated carcinogenesis in transgenic epidermis expressing the dominant negative TGFbetaRII.
Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) have been found in various malignant tumors, suggesting that loss of TGFbeta signaling plays a causal role in late-stage cancer development. To test whether loss of TGFbetaRII is involved in early-stage carcinogenesis, we have generated transgenic mice expressing a dominant negative TGFbetaRII (deltabetaRII) in the epidermis. These mice exhibited an increased susceptibility to chemical carcinogenesis protocols at both early and late stages. In the current study, parameters for cell cycle progression and chromosome instability were analysed in deltabetaRII tumors. DeltabetaRII papillomas showed an increased S phase in flow cytometry. Bromodeoxyuridine (BrdU) labeling and mitotic indices in deltabetaRII papillomas also showed a threefold increase compared to papillomas developing in non-transgenic mice. When papillomas further progressed to squamous cell carcinomas (SCC), both control and deltabetaRII SCC showed similar BrdU labeling indices and percentages of S phase cells. However, deltabetaRII SCC cells showed a sixfold increase in the G2/M population. Mitotic indices in deltabetaRII SCC also showed a threefold increase compared to non-transgenic SCC. Consistent with a perturbed cell cycle, deltabetaRII papillomas and SCC showed reduced expression of the TGFbeta target genes p15 (INK4b), p21 (WAF-1) and p27 (Kip1), inhibitors of cyclin-dependent kinases (cdks). However, most deltabetaRII papilloma cells exhibited normal centrosome numbers, and deltabetaRII SCC exhibited a similar extent of centrosome abnormalities compared to control SCC (35-40% cells). Most of deltabetaRII SCC exhibited diploid chromosome profiles. These data indicate that inactivation of TGFbetaRII accelerates skin tumorigenesis at early stages by the acceleration of loss of cell cycle control, but not by increased chromosome instability.
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Department of Otolaryngology, Baylor College of Medicine, Houston, Texas 77030, USA.
He
W
W
Zhong
L
L
Li
P
P
Huang
J
J
Brinkley
B R
BR
Wang
X J
XJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002273:Carcinogens / Q000009:adverse effects / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic; D018385:Centrosome; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000078404:Epidermal Cells; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008938:Mitosis; D010212:Papilloma / Q000139:chemically induced / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects / Q000494:pharmacology; D013997:Time Factors; D025521:Tumor Suppressor Proteins
D002273:Carcinogens; D002352:Carrier Proteins; C493961:Cdkn1b protein, mouse; C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008869:Microtubule-Associated Proteins; D018125:Receptors, Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015127:9,10-Dimethyl-1,2-benzanthracene; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D001973:Bromodeoxyuridine; D013755:Tetradecanoylphorbol Acetate