Regulation of Cyclin D1 RNA stability by SNIP1

Cyclin D1 expression represents one of the key mitogen regulated events during the G1 phase of the cell cycle, while Cyclin D1 over-expression is frequently associated with human malignancy. Here we describe a novel mechanism regulating Cyclin D1 levels. We find that SNIP1, previously identified as a regulator of Cyclin D1 expression, does not, as previously thought, primarily function as a transcriptional coactivator for this gene. Rather, SNIP1 plays a critical role in co- or post-transcriptional Cyclin D1 mRNA stability. Moreover, we demonstrate that the majority of nucleoplasmic SNIP1 is present within a previously undescribed complex containing SkIP, THRAP3, BLCALF1 and Pinin, all proteins with reported roles in RNA processing and transcriptional regulation. We find that this complex, which we have termed the SNIP1/SkIP associated RNA-processing (SNARP) complex, is co-ordinately recruited to both the 3′ end of the Cyclin D1 gene and Cyclin D1 RNA. Significantly, SNIP1 is required for the further recruitment of the RNA processing factor U2AF65 to both the Cyclin D1 gene and RNA. This study demonstrates a novel mechanism regulating Cyclin D1 expression and offers new insight into the role of SNIP1 and associated proteins as regulators of proliferation and cancer.