Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle.

Abstract

The sequential transcriptional activation of cyclins, the regulatory subunits of cell-cycle-specific kinases, is thought to regulate progress through the cell cycle. Cyclins are therefore potential oncogenes, and cyclin D1 overexpression and/or amplification at its genomic locus, 11q13, are common features of several human cancers. Induction of cyclin D1 is an early response to mitogenic stimulation in several cell types, but the consequences of altered expression of this gene in human cells of epithelial origin remain undefined. We assessd the effects of alterations of cyclin D1 expression in human breast cancer cells by generating T-47D cells expressing human cyclin D1 under the control of a zinc-responsive metallothionein promoter. In cycling cells induction of cyclin D1 after zinc treatment resulted in an increase in the number of cells progressing through G1 and in the rate of transition from G1 to S phase, indicating that cyclin D1 is rate-limiting for progress through G1 phase. In cells arrested in early G1 phase after growth factor deprivation, zinc induction of cyclin D1 was sufficient for completion of the cell cycle, a process requiring growth factor stimulation in control cells. These data demonstrate a critical role for cyclin D1 in human breast cancer cell-cycle control and suggest that deregulated expression of cyclin D1 is likely to reduce dependence on normal physiological growth stimuli, thereby providing a growth advantage to tumor cells and a potential mechanism of resistance to endocrine therapy.Cell-cycle progression in mammalian cells is coordinated at a series of control points, which ensure orderly progress through the complex and tightly regulated processes necessary for cell growth and division. The central mechanism for these control points is thought to be the sequential transcriptional activation of cycin genes and consequent transient accumulation of different cyclin/cycin-dependent kinase (CDK) complexes. In synchronized or growth factorstimulated cells, cyclins C, D1, D2, D3, and E are most abundant during G1 phase (1-3), suggesting that they function during G1. The D cyclins have closely related sequences but are differentially expressed: some cells express all three genes [for example, mammary epithelial cells (4)], but many cell types express only one or two (2,5,6). Furthermore, these cyclins are not coordinately regulated but, in general, appear sequentially during progress through G1 phase (2, 6-9), suggesting that they have complementary rather than redundant functions.Regulation of cyclin D1 gene expression is closely associated with changes in the proliferation rate of breast cancer cells. Increased expression of cyclin D1 occurs within 2 hr of stimulation of T-47D breast cancer cells by peptide mitogens-for example, insulin, insulin-like growth factor I, and basic fibroblast growth factor-and is followed by induction of other G1 cyclins, cyclins D3 and E, as cells progress through G1 phase (ref. 8, unpublished data). The proportion of cells that enter S phase is...

Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling

“…Although our data do not rule out G 1 targets for retinoids in T-47D cells, we believe the critical block occurs in early G 1 . Cyclin D1, AP1 and MEK1 are all involved in regulating the G 0 / G 1 transition and G 1 progression [52][53][54]. Retinoid attenuation of MAP kinase activation, immediate early gene expression, AP1 transcriptional activity and cyclin D1 expression [55] supports our hypothesis that retinoids block cell cycle progression by disrupting the mitogenic signaling that is required for early G 1 progression (of cycling cells) or the transition from G 0 into G 1 (of quiescent cells).…”

Inhibitory effect of p21 in MCF-7 cells is overcome by its coordinated stabilization with D-type cyclins

“…Hyperphosphorylation of Rb promotes the release of the E2F family of transcription factors that then promote entry into S phase through activation of key target genes (Helin, 1998). D-type cyclins are rate limiting for the progression from G1 into S phase of the cell cycle (Ando et al, 1993;Musgrove et al, 1994). Further, expression of cyclin D1 in mouse mammary glands leads to carcinoma, indicating that cyclin D1 acts as an oncogene (Wang et al, 1994).…”

Increased cell growth and tumorigenicity in human prostate LNCaP cells by overexpression to cyclin D1

“…Induction of cyclin D1 in the human breast cancer cell line, T-47D, also increases the rate of transition from G1 to S phase and the induced cyclin D1 is su cient to allow cells to complete the cell cycle even if they are arrested in early G1 phase after growth-factor deprivation (Musgrove et al, 1994). Microinjection of antibodies or antisense plasmids into cells in mid-G1 inhibits cyclin D1 and prevents the cells from entering S phase (Baldin et al, 1993;Quelle et al, 1993;Lukas et al, 1994a,b;Tam et al, 1994;Zhou et al, 1995).…”