Overexpression of human cyclin D1 reduces the transforming growth factor beta (TGF-beta) type II receptor and growth inhibition by TGF-beta 1 in an immortalized human esophageal epithelial cell line.

Abstract

Cycin D1 has been implicated in G cell cycle Since the major regulatory events leading to mammalian cell proliferation and differentiation occur in the Go-to-Gi and/or at the G1-to-S phase transition of the cell cycle (1), the deregulated expression of G1 or G1/S phase cyclins or their related cyclin-dependent kinases (CDKs) might cause loss of cell cycle control and thus enhance carcinogenesis. The strongest connection between cyclins and carcinogenesis comes from studies on cyclin D1. The cyclin D1 gene was isolated as a gene that is rearranged and overexpressed in parathyroid adenomas (2, 3). In independent studies, cyclin D1 also rescued a G1 cyclin-defective Saccharomyces cerevisiae strain, and its expression was induced in G1 by growth factors (4, 5). Microinjection and electroporation of anti-cyclin D1 antibodies into mammalian cells revealed that cyclin D1 is essential for cell cycle progression in G1 (5, 6). Amplification and overexpression of cyclin D1 were detected in several human carcinomas, including esophageal carcinomas (6).Transforming growth factor 8s (TGF-ps) are prototypic multifunctional negative growth factors that inhibit epithelial cell proliferation by delaying or arresting progression through the late portion of G1 (7). It is believed that one of the mechanisms whereby cells undergo neoplastic transformation and escape from normal growth control involves an altered response to . Previous studies have indicated links between TGF-,B1-mediated GI growth arrest and the state of cyclins, CDKs, and the product of the retinoblastoma susceptibility gene, RB (9-13). Treatment of cells with TGF-p appears to prevent phosphorylation of RB and retains RB in the hypophosphorylated, growth-suppressive state. TGF-/31 also suppresses synthesis of CDK4, a major catalytic subunit of cyclin D1, in G1 in mink lung epithelial cells, and constitutive CDK4 synthesis in these cells leads to TGF-pl resistance (9). These results indicate that growth arrest by TGF-.81 might be mediated through the cyclins, CDKs, and RB-related pathways (9-13).To further investigate the function of cyclin D1 and its role in tumorigenesis, we have stably transfected an expression vector containing the human cyclin D1 cDNA in HET-1A cells, a human normal esophageal epithelial cell line immortalized by simian virus 40 (SV40) large tumor antigen CT antigen) (14). Oversynthesis (>10 fold) of cyclin D1 protein in clones of HET-1A cells led to an increase in colonyforming efficiency and saturation density. In addition, the clones were less responsive to growth inhibition by TGF-,81 than the parental cells or control vector cell clones. Interestingly, these clones which express increased amounts of cyclin D1 exhibited a decrease in the amount of TGF-(3 type II receptor.

Reduction of Menin Expression Enhances Cell Proliferation and Is Tumorigenic in Intestinal Epithelial Cells

“…These results are reminiscent of those described in the SV40-transformed human esophageal epithelial cell line HET-1A. In the latter, the overexpression of cyclin D1 resulted in a decreased expression of the T␤RII accompanied by the loss of growth inhibition induced by TGF␤1 (35).…”

Deregulated expression of cyclin D1 overrides antimitogenic signals

“…Furthermore, the deregulated expression of cyclin D1 in a Large T-antigen immortalized carcinoma cell line also results in resistance to TGF b -1 (Okamoto et al, 1994). However, in this study it did not appear that cyclin D1 was aecting the dierent cyclin/cdk/ inhibitor complexes, but rather caused the downregulation of the expression of the type II TGF b -1 receptor.…”

The Role of Sp1 in the Differential Expression of Transforming Growth Factor-β Receptor Type II in Human Breast Adenocarcinoma MCF-7 Cells

“…Replication error-positive colorectal cancer cells show a mutation in T␤RII coding region, which results in message instability and loss of protein (12)(13)(14). Deletion of the T␤RII gene, loss of T␤RII message, and expression of a truncated T␤RII message have also been observed in other cancer cell lines (15)(16)(17)(18)(19)(20).The human breast cancer MCF-7 cells have no detectable cell surface T␤RII and are refractory to the effects of TGF␤ (18,19). The re-expression of T␤RII in these cells restores their sensitivity to the growth inhibitory effects of TGF␤ (19).…”