Alternatively spliced forms of cyclin D1 modulate entry into the cell cycle in an inverse manner

Sawa, Hiroki; Ohshima, Teruyo Arato; Ukita, Hiroyuki; Murakami, Hiromi; Chiba, Yukie; Kamada, Hajime; Hara, Mitsuhiro; Saito, Isamu

doi:10.1038/sj.onc.1201691

Cited by 102 publications

(89 citation statements)

References 39 publications

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“…10,12 Results of our and other studies have suggested that the variant allele encoding A is a major source of variant transcript b in several kinds of cancer cell. 10,[12][13][14] Furthermore, in a variety of cancers, the CCND1 genotypes have been correlated significantly with carcinogenesis or clinical outcome. 10,14 -17 Considering the importance of cyclin D1 abnormal regulation in PCa, the present study was conducted to investigate the association between the CCND1 A870G polymorphism and the susceptibility to PCa or its disease status.…”

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confidence: 78%

“…10 -12 The splicing appears to be modulated by an A870G polymorphism at codon 242 within the conserved splice donor site of exon 4 of the gene. 10,[12][13][14] This variation in splicing by an A870G polymorphism may be associated with the difference in cyclin D1 function. 10,12 Results of our and other studies have suggested that the variant allele encoding A is a major source of variant transcript b in several kinds of cancer cell.…”

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confidence: 99%

“…10,[12][13][14] This variation in splicing by an A870G polymorphism may be associated with the difference in cyclin D1 function. 10,12 Results of our and other studies have suggested that the variant allele encoding A is a major source of variant transcript b in several kinds of cancer cell. 10,[12][13][14] Furthermore, in a variety of cancers, the CCND1 genotypes have been correlated significantly with carcinogenesis or clinical outcome.…”

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confidence: 99%

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Increased risk of prostate cancer associated with AA genotype of cyclin D1 gene A870G polymorphism

Wang

Habuchi

Mitsumori

et al. 2002

Intl Journal of Cancer

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CCND1 mRNA is alternatively spliced to produce 2 transcripts, and the splicing pattern may be modulated by a frequent A870G single-nucleotide polymorphism within the conserved splice donor site of exon 4. Several studies have suggested a significant association between the CCND1 genotype and onset or progression of various cancers. 0.679). However, in patients with high-grade or metastatic PCa, a significantly increased risk associated with the AA genotype compared to controls was observed, while no significant results were found in those with low/intermediate or localized PCa. The A allele of the CCND1 A870G polymorphism was recessively associated with susceptibility to PCa and BPH in a Japanese population, giving a 2-fold increased risk of PCa and BPH in men with the AA genotype compared to those with the GG genotype. Although the risk of PCa associated with the AA genotype appeared to contribute especially to men aged 73 years or younger and the A allele may be associated with disease status of PCa, these conjectures require validation in future studies on a larger number of subjects.

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confidence: 78%

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Increased risk of prostate cancer associated with AA genotype of cyclin D1 gene A870G polymorphism

Wang

Habuchi

Mitsumori

et al. 2002

Intl Journal of Cancer

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“…A common G to A polymorphism at codon 242 on exon 4 in the CCND1 gene has been shown to modulate splicing of the CCND1 transcript (Betticher et al, 1995). The dominant A allele preferentially generates the truncated transcript Sawa et al, 1998), which encodes a cyclin D1 protein with a longer halflife. This accumulation of cyclin D1 in the cell may promote cell proliferation and the subsequent development of colorectal cancer.…”

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Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma

et al. 2006

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Cyclin D1 (CCND1) plays a key role in cell cycle control, particularly in the transition from G 1 to S phase, which is regulated by cyclindependent kinases. A common adenine to guanine polymorphism (A870G) in the CCND1 gene has been associated with a longer-life protein and an increased risk of colorectal cancer and adenoma in some studies. Among subjects with hereditary nonpolyposis colorectal cancer, the A870G polymorphism has also been associated with a younger age of onset of colorectal cancer. We analysed 181 colorectal cancer cases and 475 matched controls and 524 adenoma cases and 517 matched controls within women in the Nurses' Health Study (NHS) cohort, 171 colorectal cancer cases and 347 matched controls and 372 adenoma cases and 712 matched controls nested within men in the Health Professionals' Follow-Up Study (HPFS) cohort, and 258 colorectal cancer cases and 415 matched controls within men in the Physicians' Health Study (PHS) cohort to assess the risk associated with the CCND1 A870G genotype. Moreover, we assessed whether CCND1 genotype modified the effect of a sporadic (nonsyndromic) family history of colorectal cancer as well as the effect of other dietary and lifestyle risk factors for colorectal cancer and adenoma. In all cohorts combined, the CCND1 polymorphism did not show statistically significant associations to risk of colorectal cancer (odds ratio (OR) for A allele carriers, 1.04; 95% confidence interval (95% CI), 0.82 -1.32) or adenoma (OR, 0.96; 95% CI, 0.79 -1.18). The CCND1 A870G genotype was associated with a modest, although nonsignificantly elevated risk of colorectal cancer (OR, 1.59; 95% CI, 0.98 -2.57) in women. In contrast, the polymorphism was not associated with increased risk of adenoma in either men or women. Among participants with the A870G genotype, a family history of colorectal cancer conferred a substantially greater risk of colorectal cancer in the women (P for interaction ¼ 0.06) and adenoma in the men (P for interaction ¼ 0.02). Current postmenopausal hormone (PMH) use was associated with a significant reduction in the risk of colorectal cancer and adenoma among women with the A870G genotype, whereas there was no effect of PMH use among those with the GG genotype. The CCND1 polymorphism appeared to confer a modest elevation in the risk of colorectal cancer among women. Moreover, the A870G genotype may enhance the protective effect of postmenopausal oestrogen use on the development of colorectal neoplasia.

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“…[23][24][25][26][27] Until recently, less consideration has been given to the function of the protein product from CCND1 trb . Sawa et al 28 have demonstrated that when overexpressed in human malignant glioma cells, the alternatively spliced forms of cyclin D1 modulate entry into the cell cycle in an inverse manner. More recent data examining constitutive expression of CCND1 tra and CCND1 trb , demonstrates that cyclin D1 TRB protein remains nuclear through out the cell cycle whereas cyclin D1 TRA is redistributed to the cytoplasm at the G 1 -S boundary.…”

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Induced expression of human CCND1 alternative transcripts in mouse Cyl‐1 knockout fibroblasts highlights functional differences

Holley

Heighway

Hoban

2004

Intl Journal of Cancer

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Splicing of human cyclin D1 (CCND1) mRNA producing transcripts a and b is modulated by a common polymorphism (A 3 G) located in a conserved splice donor region at nucleotide 870. CCND1 A/G 870 genotype is associated with tumour progression and clinical outcome in a variety of cancers. Although in vitro expression of cyclin D1 transcript a (CCND1 tra ) has been widely investigated, few studies have examined the expression of CCND1 transcript b (CCND1 trb ). We have studied the effects of inducible expression of human CCND1 trb in comparison with human CCND1 tra in a mouse fibroblast knock-out for cyclin D1 (MEF Cyl-1؊/؊ ). Inducible expression was in stable clones isolated from MEF Cyl-1؊/؊ transfectants. Induction of CCND1 tra produced a 36-kDa protein, which led to a significant increase in the proportion of cells in S-phase, as detected by BrdU incorporation after 32 hr, compared to non-induced cells (p ‫؍‬ 0.012). Clones induced to express CCND1 tra exhibited a significantly increased ability to grow in serum depleted (2% FCS) medium compared to non-induced clones (p ‫؍‬ 0.0004). Induced expression of CCND1 trb in MEF Cyl-1؊/؊ transfectants produced a 31-kDa protein and resulted in no significant difference in DNA synthesis, neither did the cells acquire the ability to grow in serum-depleted conditions compared to non-induced cells. Induction of CCND1 trb significantly enhanced the ability of MEF Cyl-1؊/؊ transfectants to form colonies in soft agar, (average 30-fold increase) compared to noninduced clones or those induced to express CCND1 tra . Our data supports the emerging view that CCND1 alternate transcripts encode proteins with differing independent biological functions. We suggest that CCND1 tra encodes a protein involved in regulating mitogen responsive, anchorage-dependent G 1 progression, whereas CCND1 trb modulates the ability of the cell to grow in an anchorage-independent manner. © 2004 Wiley-Liss, Inc.Key words: cyclin D1; splicing; proliferation; adherent growthThe cyclin D1 gene (CCND1) is alternately spliced to produce transcript a (CCND1 tra ) and transcript b (CCND1 trb ), both transcripts have been detected in a variety of tissue types. 1-4 CCND1 tra is identical to the originally described cyclin D1 cDNA, however, CCND1 transcript b (CCND1 trb ) fails to splice at the exon 4/intron 4 boundary, does not contain exon 5 and terminates downstream of exon 4. 1,5 We were first to demonstrate that a single nucleotide polymorphism (SNP) within the splice donor region of CCND1 exon 4 modulates relative CCND1 transcript levels in normal and tumour tissues and also that patient genotype is associated with tumour progression and clinical outcome in lung cancer and squamous cell carcinoma of the head and neck. 1,4,6 A growing body of data supports the view that CCND1 A/G 870 alleles modulate splicing and that CCND1 A/G 870 genotype is associated with susceptibility and modification of clinical outcome in a wide variety of cancers. 1,4,6 -14 The association of a particular genotype with disease inciden...

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Alternatively spliced forms of cyclin D1 modulate entry into the cell cycle in an inverse manner

Cited by 102 publications

References 39 publications

Increased risk of prostate cancer associated with AA genotype of cyclin D1 gene A870G polymorphism

Increased risk of prostate cancer associated with AA genotype of cyclin D1 gene A870G polymorphism

Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma

Induced expression of human CCND1 alternative transcripts in mouse Cyl‐1 knockout fibroblasts highlights functional differences

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