The cyclin D1b splice variant: an old oncogene learns new tricks

Abstract

The function of cyclin D1 as a positive regulator of the cell cycle and proto-oncogene has been well established. Cyclin D1 elicits its pro-proliferative function early in G1 phase, through its ability to activate cyclin dependent kinase (CDK) 4 or 6. Active CDK4/6-cyclin D1 complexes phosphorylate substrates that are critical for modulating G1 to S phase progression, and in this manner promote cellular proliferation. Emerging data from a number of model systems revealed that cyclin D1 also holds multiple, kinase-independent cellular functions. First, cyclin D1 assists in sequestering CDK inhibitors (e.g. p27kip1), thus bolstering late G1 CDK activity. Second, cyclin D1 is known to bind and modulate the action of several transcription factors that hold significance in human cancers. Thus, cyclin D1 impinges on several distinct pathways that govern cancer cell proliferation. Although intragenic somatic mutation of cyclin D1 in human disease is rare, cyclin D1 gene translocation, amplification and/or overexpression are frequent events in selected tumor types. Additionally, a polymorphism in the cyclin D1 locus that may affect splicing has been implicated in increased cancer risk or poor outcome. Recent functional analyses of an established cyclin D1 splice variant, cyclin D1b, revealed that the cyclin D1b isoform harbors unique activities in cancer cells. Here, we review the literature implicating cyclin D1b as a mediator of aberrant cellular proliferation in cancer. The differential roles of cyclin D1 and the cyclin D1b splice variant in prostate cancer will be also be addressed, wherein divergent functions have been linked to altered proliferative control.

Figure 1

The cyclin D1 transcript is subject to alternative splicing. Alternative splicing is known to occur at the exon4/intron 4 boundary. Effective splicing at this junction results in the well-characterized cyclin D1 product (bottom left), which contains discrete motifs that regulate cell cycle control, subcellular localization, and transcriptional regulation. Failure to splice at the exon4/intron 4 boundary results in the cyclin D1b protein product, which harbors a divergent C-terminus (hatched region). The G/A870 polymorphism (circled) is thought to influence the splicing event.

Figure 2

Cell cycle functions of cyclin D1.

Figure 3

D-type cyclins regulate androgen receptor function in prostate cancer cells. A) Cyclin D1 is induced following androgen stimulation, and acts through discrete mechanisms to both promote cell cycle progression and attenuate androgen receptor (AR) activity (left panel). These control mechanisms are hypothesized to modulate the strength and duration of the androgen response (right panel). B) The cyclin D1b variant harbors enhanced oncogenic function as compared to cyclin D1, and interrogation of cell cycle function suggests that cyclin D1b may impinge on additional factors to promote proliferation. In the context of prostate cancer, compromised ability of cyclin D1b to modulate AR function may disrupt modulation of the androgen response, and yield an enhanced proliferative response.