Cyclin D1: polymorphism, aberrant splicing and cancer risk

Abstract

The cyclin D1 proto-oncogene exercises powerful control over the mechanisms that regulate the mitotic cell cycle, and excessive cyclin D1 expression and/or activity is common in human cancers. Although somatic mutations of the cyclin D1 locus are rarely observed, mounting evidence demonstrates that a specific polymorphism of cyclin D1 (G/A870) and a protein product of a potentially related alternate splicing event (cyclin D1b) may influence cancer risk and outcome. Herein, we review the epidemiological and functional literatures that link these alterations of cyclin D1 to human tumor development and progression.

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

“…Yet to date, none of the mouse mutant models in the Smad family spontaneously develop HCC. Antiproliferative responses of TGF-b occur primarily by inhibition of G 1 -S phase transition through activation of pRb, Cdk inhibitors, p15 and p21, as well as inhibition of c-Myc, Cdk2, Cdk4, cyclin E, cyclin A and cyclin D1 (Sherr, 1996;Siegel et al, 2003;Mishra et al, 2005;Knudsen et al, 2006). Smad function is highly dependent upon adaptor proteins such as embryonic liver fodrin (ELF), SARA and microtubules (Tsukazaki et al, 1998;Tang et al, 2003;Mishra et al, 2005).…”

Diazoxide-Mediated Growth Inhibition in Human Lung Cancer Cells via Downregulation of β-Catenin-Mediated Cyclin D1 Transcription

“…Evidence of the oncogenic potential of Cyclin D1 is provided by studies with numerous models in which the elevated expression of Cyclin D1 shortens the G1 phase of the cell cycle and enhances malignant transformation [14,23]. An overexpression of Cyclin D1 blocked diazoxide-decreased H1299 cell growth, demonstrating that Cyclin D1 plays a major role in diazoxide-inhibited cell proliferation in H1299 cells.…”

“…To address the mechanisms of diazoxide-reduced cell growth, we investigated the effect of diazoxide on the expression of the Cyclin D family proteins (Cyclin D1, D2, and D3) and their corresponding kinases (CDK4 and CDK6), which are involved in the regulation of cell cycle progression and mitogenic signals [14,20]. As depicted in Fig.…”

“…It is now well known that abnormalities in many positive and negative modulators of the cell cycle are frequent in many cancer types, including lung carcinomas [12,13]. Cyclin D1, a member of the Cyclin D family, regulates the initial G1-to-S transition by inhibiting Rb and activating E2F proteins, and it contributes to cell apoptosis, proliferation, and differentiation [14]. Cyclin D1 is amplified and/or overexpressed in a number of human cancers, including breast carcinoma and B cell and T cell malignancies, and contributes to tumor cell growth [14][15][16].…”

“…Cyclin D1, a member of the Cyclin D family, regulates the initial G1-to-S transition by inhibiting Rb and activating E2F proteins, and it contributes to cell apoptosis, proliferation, and differentiation [14]. Cyclin D1 is amplified and/or overexpressed in a number of human cancers, including breast carcinoma and B cell and T cell malignancies, and contributes to tumor cell growth [14][15][16]. Accumulated evidence indicates that there is extensive cross-talk between the transcriptional and posttranscriptional regulation of Cyclin D1 expression and its biological functions.…”