Regulation of cyclin D1 RNA stability by SNIP1

TY - JOUR

T1 - Regulation of cyclin D1 RNA stability by SNIP1

AU - Bracken, Cameron P.

AU - Wall, Steven J.

AU - Barré, Benjamin

AU - Panov, Kostya I.

AU - Ajuh, Paul M.

AU - Perkins, Neil D.

PY - 2008/9/15

Y1 - 2008/9/15

N2 - Cyclin D1 expression represents one of the key mitogen-regulated events during the G(1) phase of the cell cycle, whereas Cyclin D1 overexpression 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 cotranscriptional or posttranscriptional Cyclin D1 mRNA stability. Moreover, we show that the majority of nucleoplasmic SNIP1 is present within a previously undescribed complex containing SkIP, THRAP3, BCLAF1, 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 complex, is coordinately 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 shows 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.

AB - Cyclin D1 expression represents one of the key mitogen-regulated events during the G(1) phase of the cell cycle, whereas Cyclin D1 overexpression 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 cotranscriptional or posttranscriptional Cyclin D1 mRNA stability. Moreover, we show that the majority of nucleoplasmic SNIP1 is present within a previously undescribed complex containing SkIP, THRAP3, BCLAF1, 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 complex, is coordinately 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 shows 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.

KW - Bone Neoplasms

KW - Cell Cycle

KW - Cell Line, Tumor

KW - Cyclin D1

KW - Gene Expression Regulation, Neoplastic

KW - HeLa Cells

KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - Nuclear Proteins

KW - Osteosarcoma

KW - Polymerase Chain Reaction

KW - RNA, Messenger

KW - RNA, Neoplasm

KW - RNA, Small Interfering

KW - Ribonucleoproteins

KW - Transcription, Genetic

KW - Transfection

U2 - 10.1158/0008-5472.CAN-08-1217

DO - 10.1158/0008-5472.CAN-08-1217

M3 - Article

C2 - 18794151

SN - 0008-5472

VL - 68

SP - 7621

EP - 7628

JO - Cancer Research

JF - Cancer Research

IS - 18

ER -