D-type Cyclins and Cancer by Philip W. Hinds & Nelson E. Brown

Author:Philip W. Hinds & Nelson E. Brown
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

3.12 Functional Interactions Between Cyclin D1 and Transcription Factors In Vivo

Several functional interactions between cyclin D1 and TFs have been assessed for their biological significance in vivo. So far, the interactions between cyclin D1 and PPARγ, DMP1, ERα, C/EBPβ, and AR have been examined in vivo. The interaction with PPARγ was already described under “transcriptional regulation of fat metabolism .”

One of the first TFs shown to bind cyclin D1 was cyclin D-interacting myb-like protein 1 (designated DMP1) [47, 48]. DMP1 could bind cyclin D1 and was also phosphorylated by cyclin D-dependent kinases. DMP1 binds the DNA consensus sequence CCCG(G/T)ATGT in order to activate transcription. It was shown that DMP1 activity was antagonized by cyclin D1, an effect that was independent of cyclin D1-associated kinase activity [48]. In subsequent studies, DMP1 was shown to be an haploinsufficient tumor suppressor protein that, upon reduced expression, accelerated Myc-induced lymphomagenesis with a concomitant reduction in the mutational rates of p53 within the tumors [131]. Regarding the functional interaction between DMP1 and cyclin D1 in vivo, a cooperation between cyclin D1 loss and DMP expression was observed in breast cancer [132]. DMP1 activates both the Arf and Ink4a promoters and, consequently, induces apoptosis or G2/M cell cycle delay in normal cells [132]. Cyclin D1-induced Ink4a/Arf expression was indeed dependent on DMP1, since induction of Ink4a/Arf expression was not detected in DMP1-deficient or DMP1-depleted cells [132]. Arf/Ink4a expression was increased in premalignant mammary lesions derived from DMP1 +/+ , MMTV-cyclin D1, and DMP1 +/+ , and MMTV-D1 (T286A) mice but was significantly downregulated in those lesions derived from DMP1-deficient mice. Selective DMP1 deletion was found in 21% of the MMTV-D1- and MMTV-cyclin D1 (T286A)-driven mammary carcinomas, and DMP1 heterozygous status significantly accelerated mouse mammary tumorigenesis. Recently, the DMP1 locus was shown to generate two splice variants, a tumor-suppressive DMP1α (p53-dependent) and an oncogenic DMP1β (p53-independent). The DMP1β/DMP1α ratio seems to increase with the neoplastic transformation of breast epithelial cells [133]. This process is associated with high DMP1β protein expression and a shorter survival of breast cancer patients. Like DMP1 , ARF is also frequently inactivated by aberrant splicing in human cancers [134]. The functional significance of these alternatively spliced forms and their role in transcription remains to be explored.

Early studies had shown that cyclin D1 can bind to C/EBPβ and augment C/EBPβ-dependent reporter activity, contributing to the regulation of a common gene signature in human breast cancers [66]. Cyclin D1 binds the C/EBPβ isoform, LAP1, and this interaction leads to an activation of the transcriptional function of LAP1, after relieving its auto-inhibited state [135]. In addition, cyclin D1 and C/EBPβ co-localized to the CEBP site of the HSC70 promoter in differentiated mammary epithelial cells. Re-expression of LAP1 restored the ability of C/EBP β-deficient mammary epithelial cells to differentiate and did so in a manner that was dependent on cyclin D1.

Genetic studies have confirmed the biological significance of cyclin D1 in both ERα signaling in the mammary gland [136] and AR signaling in the prostate gland [99].

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