CCND1 (B-cell leukemia/lymphoma 1)

2015-04-01 Shreya Sarkar , Chinmay Kumar Panda Affiliation

Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India; ckpanda.cnci@gmail.com

Identity

HGNC

CCND1

LOCATION

11q13.3

IMAGE

LEGEND

The figure shows the chromosomal location of CCND1 (Red line). Image courtesy genecards.org

IMAGE

LEGEND

CCND1 (B-cell leukemia/lymphoma 1) Top: Probe bA30016 - Courtesy Mariano Rocchi; Bottom: Hybridization with Vysis LSI Cyclin D1 (11q13) SpectrumOrange/Vysis CEP 11 SpectrumGreen probe (Abbott Molecular, US) showing CCND1 on 11q13.3 (red signals) - Courtesy Adriana Zamecnikova.

LOCUSID

595

ALIAS

BCL1,D11S287E,PRAD1,U21B31

FUSION GENES

Show Gene Fusions

Abstract

Review on CCND1, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Diagram shows the different transcripts of CCND1 (BROWN, BLUE AND MAROON BOXES). Beginning of boxes represents transcription start sites. Filled areas represent translated regions. The brown box representing transcript CCND- 001 forms the full length, active protein. Image adapted from Ensembl.org

Description

Located in the long (q) arm of chromosome 11 in the 13th band, the length of the CCND 1 gene is about 13.38 Kb (precisely 13,388 bases), contains 5 exons and is arranged in a telomere to centromere orientation.

Transcription

According to Ensembl, the full length, functional transcript of CCND1 (Transcript ID ENST00000227507) is 4307 bp in length, encoding 5 coding exons. From the total of 6 transcripts generated, only two are protein coding.

Pseudogene

None reported.

Proteins

Schematic diagram of full length CCND1, showing different domains. Adapted from PDB P24385.

Data origin/ Colour codes: Data in Green originates from UniProtKB.; Data in blue originates from PDB. Secstruc- Secondary structure projected from representative PDB entries onto the UniProt sequence. a. Red box- Helix. b. Grey tube- Coil. Data in red indicates combined ranges of Homology Models from SBKB and the Protein Model Portal.

Description

The full length CCND1 protein has a length of 295 amino acids, having a molecular weight of 33729 Da. CCND1 is a member of the cyclin family, Cyclin D subfamily and contains 1 cyclin N-terminal domain.

The RNA expression data of CCND1 based on data from BioGPS, Illumina Human BodyMap, and SAGE, with SAGE tags from CGAP,

Figure shows RNA expression data (presence/absence) for RNA genes is according to H-InvDB, NONCODE, miRBase, and RNAdb. The expression images based on data from BioGPS, Illumina Human BodyMap, and SAGE, with SAGE tags from CGAP.

BioGPS

76 normal tissues were used and compartments hybridized against HG-U133A, with Affeymetrix MAS5 algorithm used in array processing.

Illumina body map

Transcripts were mapped to genes from 16 normal human tissues by sequencing. Cufflinks program was used to calculate Fragments per Kilobase of exon per Million fragments mapped (FPKM) and rescaled by multiplying FPKM by 100 and calculating the root.

CGAP: SAGE Normal

For Serial Analysis of Gene Expression (SAGE) of 19 normal human tissues, Hs frequencies and Hs libraries in CGAP datasets are mined for information regarding the number of SAGE tags per tissue. Unigene clustering was applied to Tags, followed by a particular gene by mining Hs best gene, Hs best tag and Hs GeneData. The number of appearances of the corresponding tag divided by the total number of tags in libraries derived from that tissue was used in calculating the level of expression of a particular gene, which were then rescaled by making the genomic mean of all tissues equal.

Intermediate between log and linear scales are normalized intensities drawn on root scale, with values not comparable between datasets (i.e. Microarray, RNAseq and SAGE).

Figure courtesy: genecards.org.

BioGPS

76 normal tissues were used and compartments hybridized against HG-U133A, with Affymetrix MAS5 algorithm used in array processing.

Illumina body map

CGAP: SAGE Normal

Intermediate between log and linear scales are normalized intensities drawn on root scale, with values not comparable between datasets (i.e. Microarray, RNAseq and SAGE).

Figure courtesy: genecards.org.

Presentation of protein expression images for 35 tissues, fluids and cells. Data sources:

1- MOPED - Eugene Kolker, Bioinformatics & High-throughput Analysis Lab, Seattle Childrens Research Institute
.

2- PaxDb - Christian von Mering, Bioinformatics Group, Institute of Molecular Life Sciences, University of Zurich.

3- MAXQB - Matthias Mann, Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Germany.

The data was normalized as follows:

For each sample, ppm protein values were calculated, if not provided so by data sources. For each sample from MAXQB, iBAQ expression values were divided by sum of values of each sample, and multiplied by 1,000,000. For all samples, data was gene centrically aggregated by summing expression values of all isoforms for each gene. For better visualization of graphs, expression values are drawn on a root scale, which is an intermediate between log and linear scales as used for our mRNA expression graphs (PMID 12519968).

Localisation

Nuclear, cytoplasmic and membrane.
NOTE: Accumulation of CCND1- CDK4 complexes occur in the nuclear membrane, which are then transported to the nucleus through interactions with KIP-CIP family member proteins (By similarity, a LaBaer et. al.,1997).

EXPRESSION IN TISSUES:

TOP: Cyclin D1 overexpression in keratoacanthomas (KAs) and squamous cell carcinomas (SCCs). CCND1 (brown), counterstain hemalaun (blue). (a) Normal skin and (b) actinic keratosis, a precursor lesion of SCCs. (c-f) Representative KAs (c) Higher magnification of a different tumor (d); medium expression (e); and low expression (f) of cyclin D1. Bar=50 micro-m. Image courtesy Burnworth et. al., 2006.

MIDDLE: The figure shows the localization of CCND1 in Ramos cells. Image courtesy Abcam ®

BOTTOM: EXPRESSION DURING CELL CYCLE:

Image shows the levels expression of CCND1 during different phases of the cell cycle (left panel) and the function associated in each phase (right). Image courtesy kinexux.ca (left) and Yang et. al., 2006 (right).

Function

CCND1 binds and activates the G1 cyclin dependent kinases, Cdk4 and Cdk6. The complex then phosphorylates and inhibits members of the retinoblastoma (RB) family of protein including RB1, thereby regulating the G1/S transition in the cell cycle (Kato et al., 1993).
CCND1 has a kinase-independent function of sequestering CDK inhibitors such as p27 Kip1 and p21Cip1and promoting efficient activation of Cyclin E/CDK2-containing complexes (Polyak et al., 1994; Sherr and Roberts, 1999).
CCND1 phosphorylates Smad3 and inhibits its transcriptional activity and antiproliferative function (Matsuura et. al., 2004).

Homology

The CCND1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog (According to Homologene, NCBI).

Top: String model depicting probable binding partners on CCND1. Image adapted from string-db.org; Bottom: The figure shows the different proteins with which CCND1 interact and the different functions that result from such interactions. Picture courtesy: Pestell, 2013.

Gene tree of CCND1 Human has been encircled in red. Adapted from ensembl.org.

Mutations

Figure shows the predicted miRNA binding sites in the 3 UTR of CCND1. Image courtesy TargetScan 6.2.

(click to zoom in)
1- Figure represents the types and percentages of various of mutations observed in CCND1. Image adapted from COSMIC gene analysis.

2- Mutations/ Variations in the different regions of CCND1 (lager, functional variant). Adapted from ensemble.org.

3- Mutations and copy number variations of CCND1 in different organs. Red bar: Loss. Grey bar: Gain. Adapted from COSMIC gene analysis.

Epigenetics

CCND1 and miRNAs:

miR365
in Gastric cancer cell line BGC-823
Binds to 3 UTR of CCND1 in gastric cancer. miR-365 markedly decreased the expression (mRNA and protein) of CCND1. Conversely, miR365 knockdown repressed cell growth, which can be overcome by CCND1 over-expression. Similar inverse co-relation was obtained between miR-365 and CCND1 expression in patient samples. (Long-Guo et. al., 2013).
in Vascular smooth muscle cell (VSMC)
miR-365 suppresses CCND1 significantly in mRNA and protein levels in primary rat VSMC. CCND1 is a direct target of miR-365 in vascular smooth muscle cells, as shown by significant inhibition of the luciferase activity of wild type CCND1 3 UTR, but not the mutant cyclinD1 3 UTR with the mutant biding site of miR-365 (Zhang et. al., 2014). CCND1 is a potential target of mir-365 through direct binding. (Kim et. al., 2014).
in Colon cancer
miRNA directly binds to the 3UTR of CCND1, proved by luciferase reporter assay. Transfection of miR365 significantly decreased CCND1 expression in HT29 and LoVo cells. Pearsons co-relation between miR-365 levels and CCND1 expression by qRT-PCR and western blot showed that they were inversely correlated (Nie et. al., 2012).

miR-338-3p in Hepatocyte cell line LO2
miR-338-3p binds at two regions in the 3 UTR of CCND1( mainly at the site spanning nucleotides 2397-2403). Overexpression of miR-338-3p downregulates endogenous CyclinD1 protein, while inhibition upregulates CyclinD1 protein, without any change in CCND1 mRNA levels. miR-338-3p post-transcriptionally regulates CCND1 (Fu et. al., 2012).

miR-19a in Human umbilical vein endothelial cells (HUVECs)
miR-19a binding site (nucleotides 1,778-1,785 in human CCND1) identified by sequence alignment, which is highly conserved among different species. Binding of miR-19a to 3 UTR of CCND1 verified by luciferase assay. CCND1 protein expression markedly reduced upon over-expression of miR-19a, although no change in RNA expression. miR-19a post-transcriptionally regulates CCND1 expression (Qin et. al., 2010).

miR-490-3p in A549 Lung cancer cell line
miR-490-3p binds to 3 UTR of CCND1. Over-expression decreased the expression of CCND1, both at the RNA and protein levels (Gu et. al., 2014).

miR-302 in Endometrial cell line Ishikawa
Directly targets CCND1 and significantly inhibited protein expression (Yan et. al., 2014).

miR-449-a in Gastric cancer cell line SGC7901
miR-449a inhibited SGC7901 cells proliferation and enhanced cisplatin chemosensitivity by downregulating expression of CCND1, respectively, via directly targeting the 3-untranslated regions of CCND1 mRNA (Hu et. al., 2014).

miR-16 in Bladder cancer cell line TCHu-1
Binding of miR16 to 3 UTR of CCND1 and its reduced expression was validated by luciferase assay, while the reverse result was obtained by mutation of the conserved miR-16 binding motif. Overexpression of miR-16 in TCHu-1 cells led to reduced CCND1 protein expression, whereas its inhibition led to an increased expression of CCND1 (Jiang et. al., 2013).

miR-9 in Gastric cancer
Databases indicated potential binding site of miR-9 with high complementarity at CCND1 39-UTR (bases 2974-2995), which was validated by luciferase reporter assay. Significant inverse correlation between miR-9 expression and CCND1 transcript levels in gastric cancer tissues and cell lines. Overexpression of miR9 in gastric cancer cell lines SGC-7901 and AGS resulted in reduced RNA and protein expression of CCND1, whereas knockdown of miR-9 produced the opposite result, proving that miR-9 considerably inhibited the expression of CCND1 through post-transcriptional repression. Results validated by in-vitro experiments (Zheng et. al., 2013).

miR-195 in Glioma
Analysis using publicly available algorithms (TargetScan, Pictar, miRANDA) indicates that CCND1 is a predicted target of miR-195, which was validated by overexpression of miR- 195, which reduced, but inhibition of miR-195 increased, the luciferase activity of CCND1-39UTR in a consistent and dose-dependent manner. Upregulation of miR-195 decreased, but inhibition of miR-195 increased, the expression levels of CCND1 in LN18 and T98G glioma cells. The findings were also validated in a model system in mice (Hui et. al., 2013).

miR-155 in Human extravillous trophoblast derived HTR-8/SVneo cells
Bioinformatics analysis showed that, at the 3 untranslated region (UTR) of CCND1, six bases are complementary to the seed region of miR-155. Luciferase assays and CCND1 3UTR transfection assays validated that CCND1 3UTR was the target of miR-155 in HTR-8/SVneo cells. Overexpression of miR-155 in HTR-8/SVneo cells reduced the level of CCND1 protein (Dai et. al., 2012).

miR-143 in Mesenchymal stem cells from the bone marrow of male Fischer 344 rats
Ectopic expression of miR-143 also increased CCND1 in the native MSC as compared with scramble transfected cells .On the contrary, pre-treatment of AAMSC with miR-143 specific antagomir significantly abolished CCND1 expression (Lai et. al., 2012).

miR-21
in Mouse liver regeneration
Cyclin D expression and G1 phase transition of hepatocytes after 2/3 PH depend on induced miR-21 expression. Knockdown of miR-21 impaired progression of hepatocytes into S phase of the cell cycle, mainly through a decrease in levels of cyclinD1 protein, but not Ccnd1 mRNA, whereas increased miR-21 expression facilitated CCND1 translation in the early phase of liver regeneration (Ng et. al., 2012).
in Renal cancer
miR-21 controlled the expression of CCND1 through NF?B-dependent transcription and mediated renal cancer cell proliferation by CCND1 (Bera et. al., 2013).

miR-520-b in Hepatoma cell lines
miR520-b directly targets the 3 UTR of CCND1; proved by dual luciferase reporter system. Down-regulation of protein levels of CCND1 occurred on over-expression of miR520-b in HepG2 and H7402 cells, while the over-expression occurred on inhibition in miR520-b. Tumors in mice over-expressing miR520-b also showed lower CCND1 expression (Zhang et. al., 2012).

miR-193b in Melanoma
TargetScan showed that miR193b binds to the 3UTR of CCND1, which was proved by luciferase reporter assay. miR-193b over-expression led to nearly 50% reduction in CCND1 mRNA and protein levels in Malme-3M cells than in control (Chen et. al., 2010).

miR-17/20 in Breast cancer
Levels of the miR-17-5p/miR-20a miRNA cluster were inversely correlated to CCND1 abundance in human breast tumors and cell lines. miR 17/20 negatively regulates the expression of CCND1 by binding to a conserved 3UTR region (nucleotides 2,109-2,117) of the gene (Yu et. al., 2008).

miR-20 and miR106-a in Spermatogonial stem cells (SCC)
They promote renewal at the post-transcriptional level via targeting CCND1. Knockdown of CCND1 results in renewal of SCCs (He et. al., 2013).

miR-503 in Endometrioid endometrial cancer (EEC)
Binds to 5 UTR of CCND1 and its expression is inversely co-related with CCND1 in EEC tissues and cell lines (Xu et. al., 2013).

miR-449b in SW116 colon cancer stem cell
Transfecting pre-miR-449b and inhibiting miR-449b altered protein expression levels of CCND1 (Fang, 2013).

miR-15a and miR16-1 in Osteosarcoma
They bind to 3-UTR of CCND1 and suppress transcription of CCND1 (Cai et. al., 2012).

miR-138 in Nasopharyngeal carcinoma
CCND1 is a novel direct target of miR138. mRNA levels of CCND1 were inversely correlated with miR-138 expression (Liu et. al., 2012).

miR-34a in A549 cell line
Ectopic expression of miR-34a reduces both mRNA and protein levels of CCND1 by targeting the 3-untranslated mRNA region of CCND1 (Sun et. al., 2008).

miR-29a in Breast cancer cell lines
Over-expression of miR29a down-regulation of CCND1 expression in MDA-MB-453 cells, whereas in MCF-10A cells with Mir-29a knockdown, CCND1 was up-regulated (Wu et. al., 2013).

miR-7 in Colorectal cancer cell lines
Over-expression of miR-7 significantly decreased CCND1 expression (Xu et. al., 2014).

miR-545 in Lung cancer
miR-545 caused cell cycle arrest at the G0/G1 phase and induced cell apoptosis in lung cancer cells by targeting CCND1. The effects of CCND1 down-regulated by miR-545 were similar to those caused by siRNAs of CCND1 and over-expression of CCND1 could abolish the miR-545-induced inhibition of cell proliferation (Du et. al., 2014).

miR-125b in Melanoma
Cells over-expressing miR-125b exhibited reduced expression of CCND1 (Nyholm et. al., 2014).

miR-147 in Colon and lung cancer cells.
Transfection of miR147 led to down-regulation of CCND1 (Lee et. al., 2014).

Implicated in

Entity name

t(11;14)(q13;q32)/B-cell malignancies CCND1/ IgH

Disease

The t(11;14) is mainly found in mantle cell lymphoma; also in: B-prolymphocytic leukaemia, plasma cell leukaemia, splenic lymphoma with villous lymphocytes; rarely in: chronic lymphocytic leukaemia, multiple myeloma

Prognosis

according to the disease.

Cytogenetics

Complex karyotypes.

Hybrid gene

5 CCND1 translocated on chromosome 14 near JH (junctions genes of IgH) and C in 3.

Fluorescence in situ hybridization (FISH) for identification of t(11;14)(q13;q32) chromosomal translocation in metaphase nuclei. Orange probe represents CCND1 (chromosome 11q13), green represents IGH (chromosome 14q32). Fusion signals representing translocations are encircled in white. Image courtesy Ghielmini et. al., 2009.

Fusion protein

no fusion protein, but promoter exchange; the immunoglobulin gene enhancer stimulates the expression of CCND1.

Oncogenesis

Overexpression of CCND1 accelerates the cell transit through the G1 phase (Williams et. al., 1993, Williams et. al., 1994, Rimokh et. al., 1994, Wlodarska et. al., 1994, de Boer et. al., 1997, Stilgenbauer et. al., 1998, Donnellan et. al., 1998, Li et. al., 1999, Wlodarska et. al., 2004, Sander et. al., 2008).

Entity name

t(11;19)(q13;p13) CCND1 / FSTL3

Note

Found in a case of chronic lymphocytic leukaemia (Hayette et al., 1998).

Entity name

Acute Lymphoblastic Leukemia (ALL)

Note

Routinely used ALL drugs: Routinely used drugs failed to bind to CCND1 in in vitro docking studies (Jayaraman et. al., 2014).

Entity name

Adrenocortical tumors (AC)

Note

CCND1 was over-expression in 31.0% (13/42) in AC tumors compared to 17.5 % (4/23) in normal adrenal samples. Similarly, mRNA of CCND1 was significantly over-expressed in AC compared to normal samples (Mitsui et. al., 2014).

Entity name

B cell neoplasia

Note

Strong CCND1 mRNA over-expression was detected in mantle cell lymphomas (23 of 23), hairy cell leukemias (5 of 19), and multiple myelomas (7 of 23) with particularly high levels in 2 of the latter cases. Intermediate CCND1 transcripts were detected in multiple myeloma (5 / 23), hairy cell leukemia (7 / 19) Low of no CCND1 was detected in B -cell chronic lymphocytic leukemias (10 / 10), follicular lymphomas (9 / 9), mucosa associated lymphoid tissue lymphomas (5 / 5) and reactive lymphoid tissues (Specht et. al., 2002).

Entity name

Biliary Intraepithelial Neoplasia (BilIN) / Pancreatic Intraepithelial Neoplasia (PanIN)

Note

Immunohistochemical expression of CCND1 was absent or focal in nonneoplastic epithelium of the bile ducts and the pancreatic ducts, and were occasionally observed in BilIN-1 and PanIN-1 and more frequently in BilIN-2/3 and PanIN-2/3. No significant difference was obtained between expression of BilIN and PanIN in semi-quantitative analysis (Sato et. al., 2014).

Entity name

Bladder cancer

Note

Increased CCND1 levels were not correlated with OS with a pooled HR estimate, but were significantly correlated with progression-free survival (Ren et. al., 2014)
Over-expression of Pin X1 in T24 cells leads to greater than 2 fold increase in mRNA expression of CCND1 than in control cell, with similar results obtained by Western blotting. A significant correlation between the immune-histochemical expression of PinX1 and CCND1 was also observed in the UCB tissues (Liu et. al., 2013).
Ursane triterpenoid isopropyl 3?-hydroxyurs-12-en-28-oat (UA17) (Natural compound) : Protein level of CCND1 was down-regulated in a dose-dependent manner when treated with UA17or Cisplatin in NTUB1 cells. Enhanced decrease of level of CCND1 when treated with a combination of Cisplatin (20 ?M) + UA17 (20 ?M) (Lin et. al., 2014)
Metformin : Treatment with metformin leads to reduction in expression of CCND1 in a dose-dependent manner. Metformin treatment also markedly reduced the expression of CCND1 in Human Bladder Tumor Xenografts in Nude Mice compared to control (Zhang et. al., 2013).

Entity name

Breast cancer

Note

CCND1 induction of Dicer coordinates microRNA biogenesis by its transcriptional targeting (Yu et. al., 2013).
Enhanced expression of Vav1 led to the elevation of CCND1 and the progression of cell cycle (Du et. al., 2014).
Tea polyphenols (Natural compound): Tea polyphenols did not significantly alter the expression of CCND1 in breast cancer cell lines (Chen et. al., 2014).
Acylglycerol kinase (AGK) over-expression led to concurrent increase in levels of CCND1 (Wang et. al., 2014).
Activation of Notch-1 signaling up-regulated expression of CCND1 through NF-kB (Li et. al., 2014).
Panepoxydone (Natural compound): CCND1 was down-regulated by dose-dependent treatment of Panepoxydone (Arora et. al., 2014).
Gallotannin (Natural compound): Nanostring and qPCR data showed that CCND1 was exclusively downregulated on treatment with gallotannin in triple negative breast cancer (Zhao et. al., 2014).
Progesterone induced the assembly of a transcriptional complex among AP-1, Stat3, PR, and ErbB-2 at the CCND1 promoter, which functions as an enhanceosome to drive breast cancer growth (Flaqué et. al., 2013).
Obatoclax analog SC-2001 : SC-2001 down-regulated CCND1 in TNBC cell lines in a dose- dependent manner (Liu et. al., 2014). Euginol (Natural compound): Treatment of euginol decreased CCND1 level 3 fold in MDA-MB-231 cells and 20 fold in MCF7 cells compared to control (Sharif et. al., 2013).
8u001ebromou001e7u001emethoxychrysin (BrMC) (Natural compound): BrMC caused a doseu001edependent reduction of CCND1 in HER2/neu over-expressing breast cancer cells (Cao et. al., 2014).
Fenofibrate : Fenofibrate decreased the expression of CCND1 in a time and dose dependent manner in Triple negative breast cancer cells (Li et. al., 2014).

Entity name

Chronic Myeloid Leukemia (CML)

Note

Resveratrol (Res) (Natural compound): Res reduced expression of CCND1 in K562 cells (Siu et. al., 2014).
Quercetin (Natural compound): CML KBM7 Cells demonstrated reduction in expression on CCND1 on treatment with quercetin ((Li et. al., 2014).

Entity name

Chronic Myeloid Leukemia (CML)

Note

Entity name

Colorectal cancer

Note

There was significant association between post-menopausal hormone therapy (HRT) and CCND1 negative-tumors, as well as significantly increased risk in CCND1 positive tumours (Brändstedt et. al., 2014).
High height and weight was associated with risk of CCND1 positive CRC in women. Increased hip circumference, high BMI, high WHR and high waist circumference was associated with CCND1 positive tumours in men (Brändstedt et. al., 2013).
CCND1 over-expression was significantly associated with both poor OS, DFS, relatively older patients (?60 years), T3,4 tumor invasion, N positive and distant metastasis (Li et. al., 2104).
Galectin-3 knockdown decreased the mRNA expression level of CCND1, whereas epirubicin significantly up-regulated their expression. Combined treatment effectively reduced the mRNA expression of CCND1 (Lee et. al., 2013).
HMGCR expression was significantly associated with expression of CCND1 (Bengtsson et. al., 2014).
CoCl2 : Treatment of COCl2 leads to dose-dependent decrease in expression of CCND1 and cell cycle arrest (Lopez-Sanchez et. al., 2014).
SW620-S and TGF-b1 : Fibroblasts induced by Colorectal cancer cells, treated with SW620-S and TGF-b-1 separately showed high expression of CCND1 (Rao et. al., 2014).

Entity name

Diffuse large B-cell lymphoma

Note

A case of diffuse large B-cell lymphoma was described, which developed within a rectal tubular adenoma with low-graded dysplasia. The mass showed positive staining of CCND1 (Genovese et. al., 2014).

Entity name

Esophageal cancer

Note

CCND1 G870A polymorphism had no significant association with esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EADC) in Caucasian or the Asian populations. However, the comparison of A vs. G in CCND1 G870A showed significant differential susceptibility to esophageal cancer, suggesting that the CCND1 G870A polymorphism has no association with esophageal cancer risk in ethnicity and histology, respectively (He et. al., 2013).
No significantly statistical differences between the two groups were observed in distribution of genotypes or alleles at CCND1 807 (Jang et. al., 2013).

Entity name

Fibrosarcoma

Note

KIOM-C (Natural compound) : Treatment of HT1080 human fibrosarcoma cells led to down-regulated expression of CCND1 compared to control (Kim et. al., 2014).

Entity name

Gastric cancer

Note

Down regulation of CCND1 by ShCCND1 in NCI-N87 cells showed significant inhibition of cell proliferation, cell motility, clonogenicity, G1 arrest and apoptosis. Results were validated by in vivo studies in mice, suggesting the possibility of developing new gastric cancer therapies using lentivirus-mediated shRNA (Seo et. al., 2014).
Resveratrol (Res) (Natural compound) : Res reduced expression of CCND1 (Yang et. al., 2013). Knockdown of P115 led to reduction in expression of CCND1, whereas its over-expression led to up-regulation of CCND1 (Li et. al., 2013).
Caudatin 3-O-?-D-cymaropyranosyl-(1 ? 4)-?-D-oleandropyranosyl-(1 ? 4)-?-D-cymaropyranosyl-(1 ? 4)- ? -D-cymaropyranoside (CGII) (Drug): CGII induced down-regulation of expression of CCND1 in a dose-dependent manner in Gastric Cancer SGC-7901 Cells (Wang et. al., 2013)
Tetramethypyrazine (TMP) (Natural compound): Expression of CCND1 gradually decreased with increasing concentrations of TMP in Gastric cancer 7901 cells (Ji et. al., 2014).

Entity name

Gastric cancer

Note

Entity name

Glioma

Note

Expression of Alpha enolase (ENO-1) inhibited the expression of CCND1 (Song et. al., 2014).

Entity name

Hairy Cell Leukemia (HCL)

Note

CCND1 displayed nuclear staining at variable intensities but with high specificity and accuracy in HCL biopsies, thus representing it as a valuable tool in the differential diagnosis of HCL and its mimics (Tóth-Lipták et. al., 2014).

Entity name

Head and neck squamous cell carcinoma

Note

Amplification, over-expression and translocation of CCND1 has been reported (Akervall et. al., 1997, Akervall et. al., 2002, Utikal et. al., 2005, Sabbir et. al., 2006). However, expression of CCND1 did not change in post-therapy tumors compared to pre-therapy (Sarkar et. al., 2014).

Entity name

Head and neck squamous cell carcinoma

Note

Entity name

Hepatocellular Carcinoma (HCC)

Note

Ectopic expression of miR-184 led to down-regulation of the SOX7 protein, resulting in up-regulation of CCND1, cell proliferation and tumorigenesis (Wu et. al., 2014). SOX7-overexpression inhibited cell growth by down-regulating CCND1, which could be over-ridden by ectopic expression of CCND1 and induction of SOX7. Over-expression of SOX7 suppressed tumor formation with down-regulation of CCND1 in vivo (Wang et. al., 2014).
Knockdown of TRIM24 led to decreased CCND1 expression (Liu et. al., 2014).
KIF14 knockdown suppresses tumor cell growth through decrease in levels of cyclins including CCND1 (Xu et. al., 2014).
Sorafenib and YC-1 : Treatment with the sorafenib and YC-1 combination led to a significant reduction in CCND1 (Kong et. al., 2014). 7. 3, 3u001eDiu001eOu001emethyl ellagic acidu001e4u001eOu001e?u001edu001exylopyranoside (JNE2). JNE2 induced down-regulation of expression of CCND1 in HepG2 cells (Zhang et. al., 2014).
SL1122-37: SL1122-37 induced down-regulation of expression of CCND1 in PLC/ PRF/5 HCC cells (Qin et. al., 2013).

Entity name

Hepatoma

Note

Over-expression of HAu001eFHIT inhibited the expression of CCND1 in the cells. In HepG2 cells which were transfected with a fullu001elength CCND1 promoteru001eluciferase reporter, cotransfection with increasing quantities of FHIT plasmid DNA caused a concentrationu001edependent inhibition of the transcriptional activity of the CCND1 promoter (Ge et. al., 2014).

Entity name

Lung Cancer

Note

1. PAX6 down-regulation led to reduction in protein levels of CCND1 (Zhao et. al., 2014).
Over-expression of Ubiquitin- conjugating enzyme E2C (UBE2C) increased expression of CCND1 in L-78 and SC-1680 cells, as well as in tumor transplants in nude mice (Tang et. al., 2014).
Met- F-AEA in combination with URB597 induced down-regulation of CCND1 and subsequent G0/ G1 cell cycle arrest (Ravi et. al., 2014).
Up-regulation of decorin led to significant decrease in expression of CCND1 (Liang et. al., 2013).
Polydatin: PD suppressed expression of CCND1 in A549 and NCIu001eH1975 lung cancer cell lines (Zhang et. al., 2014). Knockdown of JAM-A decreased protein levels of CCND1 (Zhang et. al., 2013).
Tea polyphenols (Natural compound): Epigallocatechin gallate, epicatechin gallate and theaflavin reduced the expression of CCND1 in benzo(a)pyrene-induced lung carcinogenesis in mice (Manna et al., 2009).

Entity name

Mantle Cell Lymphoma (MCL)

Note

1. Decrease in expression of CCND1 by RNSi induced partial inhibition and reduced expression of AKT and/or S6, which may in turn lead to decrease in NOXA mRNA levels (Dengler et. al., 2014).
85% were weakly positive and 15%, moderately positive with labelled streptavidin biotin, whereas 75% were weakly positive and 25% moderately positive for CCND1 with EnVision. All 20 mantle cell lymphoma cases were strongly CCN D1 positive with catalyzed signal amplification. No evidence of CCND1 immunostaining was obtained in any of the small lymphocytic lymphoma and follicular centre cell lymphoma instances with any of the three methods used (Barranco et. al., 2003).
CCND1 showed exclusive nuclear staining and directly compared with the expression observed by immunoblot analysis with the same antibody, as well as with mRNA expression and with the occurrence of genomic rearrangements within the B CL-1 locus. 12/13 MCL showed over-expression by immunohistochemistry or immunoblot, with similar results for additional 13 MCLs, indicating its importance for routine diagnostic purposes (Boer et. al., 2014).
CCND1 mRNA could be detected in 23 of 24 mantle-cell lymphomas by reverse transcription polymerase chain reaction (RT-PCR) whereas only 9 of 24 demonstrated a t(11;14) by PCR (Aguilera et. al., 1998).
In 16 of 21 cases of MCL with overt disease, the ratio of CCND1 mRNA to ?2-microglobulin mRNA was increased, but all 21 cases showed increased ratios of CCND1 mRNA to CD19 mRNA (Howe et. al., 2004)

Entity name

Melanoma

Note

Piperine (Natural compound) : Piperine induced reduction in expression of CCND1 in a dose- dependent manner in SK MEL 28 and B16 F0 melanoma cells (Fofaria et. al., 2014).

Entity name

Multiple myeloma

Note

CCND1 expression was observed in 57% cases. CCND1 positive group had significantly lower hemoglobin level than CCND1 negative group, though both groups showed no statistical significance in regard to age, gender, Durie and Salmon stage, lytic bone lesions, light chain phenotype, creatinine, calcium, lactate dehydrogenase, leukocyte and platelet count and bone marrow histology (Padhi et. al., 2013).

Entity name

Nasopharyngeal cancer

Note

No significant association was found between CCND1 G870A polymorphism and nasopharyngeal carcinoma risk in total population meta-analysis. In the subgroup meta-analysis by ethnicity, a negative association was shown in Caucasian subgroup, and no significant association in any genetic models among Asians was observed (Li et. al., 2013).
Indole-3-carbinol (I3C) : I3C induced G1 arrest by decreasing CCND1 expression (Chen et. al., 2013).

Entity name

Neuroblastoma

Note

CCND1 showed strong nuclear reactivity in a case study on Primary localized congenital sacrococcygeal neuroblastomas (SCNs) (Khandeparkar et. al., 2013).
Over-expression of n-myc downstream regulated gene 2 (NDRG2) induced down-regulation of expression of CCND1 (Zhang et. al., 2014).
A negative co-relation existed between WWOX and CCND1 expression (Nowakowska et. al., 2014)

Entity name

Odontogenic tumors

Note

Using immune-labelling of CCND1, no statistical difference was observed between primary and recurrent KOT (keratocystic odontogenic tumors), sporadic and NBCCS-KOT (nevoid basal cell carcinoma syndrome), and unicystic and solid AB (ameloblastomas) (Gurgel et. al., 2014).

Entity name

Oral cancer

Note

Expression of CCND1 in group 3 (leukoplakias exhibiting dysplasias) was significantly higher than in group 1 (normal buccal mucosa without any habits) and 2 (clinically normal mucosa from tobacco habits), expression in group 2 was significantly higher than in group and were statistically significant. CCND1 was mostly expressed in the lower third of epithelium. Highest expression was obtained in mild dysplasias, with expression consistently correlating with basilar hyperplasia among atypical morphological features (Ramakrishna et. al., 2013).
Clinico-pathological correlation showed that CCND1 over-expression was related to increase in tumor size, tumor differentiation and higher clinical stages and lymph node metastasis and adversely affected overall survival (Zhao et. al., 2014).
HPV-negative patients, heavy alcohol consumption was significantly associated with somatic copy-number alterations (SCNAs) in CCND1 (Urashima et. al., 2013).
The proportions of positive staining in well, moderately and poorly differentiated laryngeal SCC were 50, 66.7, 100%, respectively, for CCND1, and were statistically significant, with the expression being positively correlated with Ang-2 expression. Tumor grading and CCND1 were independent factors affecting laryngeal SCC patient survival by the Cox regression model of risk factors proportion analysis, which may possess clinical significance in evaluating the prognosis and guiding the clinical treatment of SCC (Liu et. al., 2013).
Knockdown of Nemo-like kinases (NLK) led to significant reduction in the levels of CCND1 (Dong et. al., 2013).
2,4-bis (p-hydroxyphenyl)-2-butenal : HPB 242 significantly decreased CCND1 expression in HN22 and HSC4 Oral squamous cell carcinoma cell lines (Chae et. al., 2014).

Entity name

Osteosarcoma

Note

Selective inhibition of Ether à go-go 1 (Eag1) led to significant decrease in expression of CCND1 (Wu et. al. 2014).

Entity name

Ovarian serious carcinoma

Note

Compared with NOT (Normal Ovarian Tissue), CCND1 expression in the OSA (ovarian serous cystadenomas) and OSC (Ovarian serous carcinoma) groups was significantly elevated. Expression of CCND1 was positively associated with lymphatic metastasis and the expression gradually increased in the NOT, OSA, OSu001eBT and OSC groups and was associated with tumor metastasis (Song et. al., 2014).

Entity name

Pancreatic cancer

Note

Silencing of Frizzled (Fz)2 by siRNA or shRNA induced significant reduction of expression on CCND1 (Tomizawa et. al., 2014).
Down-regulation of miR-196a led to decrease in expression of CCND1 via Nuclear Factor Kappa-B-Inhibitor Alpha (Huang et. al., 2014).
Diallyl trisulfide (DATS) (Natural compound) : DATS reduced levels of CCND1 and DATS-induced apoptosis was correlated with down-regulation of CCND1 protein levels in Capan-2 cells (Ma et. al., 2014).
alpha-Mangostin (Natural compound) : alpha--Mangostin led to decrease in expression of CCND1 (Xu et. al., 2014).
Pristimerin (PM) : PM treatment produced decreased expression of CCND1 in MiaPaCa-2 and Panc-1 cells (Deeb et. al., 2014).

Entity name

Plasmacytoma

Note

A solitary plasmacytoma following complete remission from an intravascular large B-cell lymphoma, stained strongly for CCND1 while the initial tumor was negative for CCND1, proving different clonal origins of the tumors (Lee et. al., 2014).

Entity name

Prostate cancer

Note

CNCD1 staining was positive (expression in .5% of tumor cells) in 64 cases (75.4%) and negative (expression in ?5% of tumor cells) in 21 cases (including 15 cases with no immunostaining) with normal prostate tissues being negative for CCND1. Patients with high grade Gleason score and perineural invasion showed significant association with CCND1 expression, but not with PSA levels or other parameters. Thus, high CCND1 expression could be a potential marker for tumor aggressiveness (Pereira et. al., 2014).
Univariate analyses showed that lymph node positivity, surgical margin positivity, non-localized tumor, age at prostatectomy and CCND1 in malignant epithelium were significantly associated with time to BF (Biochemical failure) (Rizzardi et. al., 2014).
Pifithrin (PFT) : Combination therapy with suboptimal doses of PFT-m and HT decreased expression of CCND1 (Sekihara et. al., 2013). Triptolide (Natural compound) : Triptolide induced significant decrease of expression of CCND1 through EZH2 (Tamgue et. al., 2014).

Entity name

Renal cancer

Note

Microvessicles : CCND1 protein expression in tumor tissues was markedly up-regulated by MVs released from human Whartons jelly mesenchymal stem cells (hWJ-MSCs) (Du et. al., 2014).

Entity name

Sarcoma

Note

Tea polyphenol epigallocatechin gallate (EGCG) did not alter expression of CCND1 in Sarcoma180 cells in vivo (Manna et. al., 2006)

Entity name

T-cell Acute Lymphoblastic Leukemia

Note

Resveratrol (Res) (Natural compound): Expression of CCND1 was attenuated in Res treated T-ALL CEM-C1-15 cells (Ge et. al., 2013).

Entity name

T-cell Acute Lymphoblastic Leukemia

Note

Resveratrol (Res) (Natural compound): Expression of CCND1 was attenuated in Res treated T-ALL CEM-C1-15 cells (Ge et. al., 2013).

Entity name

Uterine cervical cancer

Note

Bcl-1/Cyclin D1 alterations are associated with the development of uterine cervical carcinoma (Singh et. al., 2005).

Entity name

Various cancers

Note

Ursolic acid (UA) (Natural compound) : UA in combination with other drugs led to down-regulation of expression of CCND1 (Doudican et. al., 2014).
Salinomycin-: Salinomycin induced lowering of expression of CCND1 in Breast and prostate cancer cells (Lu et. al., 2014).

Entity name

Non-cancerous tissues

Note

Primary human cardiomyocytes: Thrombin time-dependently up-regulated CCND1 expression, with a significant response within 36-48 h (Chien et. al., 2014).
Human diploid fibroblast (HDFs): CCND1 gene was significantly up-regulated in irradiated (1 Gy) HDFs as compared to untreated control, while bothHDFs treated with Gelam honey and irradiated HDFs pre-treated with Gelam honey showed down- regulation of cyclin D1 gene as compared to irradiated HDFs. HDFs treated with Gelam honey during radiation and post-irradiation however showed significant up-regulation of cyclin D1 gene as compared to untreated control (Ahmed et. al., 2014).
Vascular smooth muscle cells: STS (sodium tanshinone IIA silate) decreased the expression of cell cycle-associated protein, CCND1 (Wu et. al., 2014)
. Vascular smooth muscle cells: PDGF-induced CCND1 mRNA and protein expression was inhibited by TGFb. PDGF-induced CCND1 expression requiring KLF5 was inhibited by TGFb via a Smad dependent mechanism, leading to G1 cell cycle arrest of VSMs (Garrido et. al., 2013).
Nuroectodermal stem cells: PGE2 (Prostaglandin E2) treatment significantly up-regulated CCND1 (Wong et. al., 2014).
Neurons: DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) reduced cellular CCND1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation (Soppa et. al., 2014).
Renal intestinal fibroblasts: Exposure of NRK-49F to resulted in reduced expression proliferation markers CCND1 in a dose and time dependent manner (Ponnusamy et. al., 2014).
Idiopathic pulmonary fibrosis (IPF): Cell cycle regulatory protein CCND1 was significantly enhanced in AEC (alveolar epithelial cell) within the remodelled fibrotic areas of IPF lungs but expression was negligible in myofibroblasts (Akram et. al., 2014).
Human Rheumatoid Arthritis Synovial Cells: The protein and mRNA levels of CCND1 decreased gradually with the increasing of thapsigargin concentration and treatment times (Wang et. al., 2014).

Entity name

Other mammals

Note

Mouse:
Rat liver fibrosis:
Decreased expression in CCND1 in the cerebellum of the hyperbilirubinemic Gunn rats led to significant increased cell cycle arrest in the late G0/G1 phase (Robert et. al., 2013).
Chicken fetal myoblasts (CFMs):
Following seventy percent partial hepatectomy (PH) in wild type (WT) mice IL-6 serum levels increased, resulting in increased CCND1 (Tachibana et. al., 2014).

CCND1 was more frequently up-regulated in mammary tumors from transgenic mice (expressing myristoylated-Akt1 (myr-Akt1) under the control of the MMTV-LTR promoter) compared to tumors from wild-type mice. Increased expression of CCND1 was incompletely dependent on Akt1 expression. Low expression of CCND1 and increased expression of Twist and Slug was observed in mammary tumors that had metastasized to secondary sites (Wu et. al., 2014).
Embelin-treated mice showed significant inhibition in tumor growth, which was associated with reduced expression of CCND1 (Huang et. al., 2014).
Nicotine significantly increased expression of CCND1 (He et. al., 2014).

In mice treated with hUCMSCs-LV-IL-21, Expression of cyclin-D1 was simultaneously low compared to control group, hUCMSCs group and hUCMSCs-LV-Vec group (Zhang et. al., 2014).
Rat:
Dairy Cow Mammary Epithelial Cells:
Treatment with leucine induced LeuRS, increasing CCND1 mRNA and protein expression (Wang et. al., 2014).

CCND1 accumulation due to differential effects of of PKC? and PKC? was likely contribute to the opposing tumor suppressive and tumor promoting activities in the intestinal epithelium (Pyfz et. al., 2014). IGF-1R activation together with EGFR co-signaling decreased the percentage of cells in G1 and enhanced cell progression into S and G2 by increases in expression of CCND1 (Alagappan et. al., 2014).
CCND1 mRNA was significantly decreased by sodium ferulate in cells under serum stimulation (Zhang et. al., 2014).
Sophocarpine inhibited the proliferation of HSCs by a decrease in the expression of CCND1 (Qian et. al., 2014).
Rat Airway Smooth Muscle Cells:
Chicken:
Increased CCND1 expression during acceleration of cell cycle at G1/ S phase in CMF was due to CARP (cardiac ankyrin repeat protein) over-expression (Ma. et. al., 2014).

Breakpoints

Bibliography

Pubmed ID	Last Year	Title	Authors

Other Information

Locus ID:

NCBI: 595
MIM: 168461
HGNC: 1582
Ensembl: ENSG00000110092

Variants:

dbSNP: 595
ClinVar: 595
TCGA: ENSG00000110092
COSMIC: CCND1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000110092	ENST00000227507	P24385
ENSG00000110092	ENST00000227507	Q6FI00
ENSG00000110092	ENST00000536559	F5H437

Expression (GTEx)

100

150

200

250

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Cell cycle	KEGG	ko04110
p53 signaling pathway	KEGG	ko04115
Wnt signaling pathway	KEGG	ko04310
Hedgehog signaling pathway	KEGG	ko04340
Focal adhesion	KEGG	ko04510
Tight junction	KEGG	ko04530
Jak-STAT signaling pathway	KEGG	ko04630
Colorectal cancer	KEGG	ko05210
Pancreatic cancer	KEGG	ko05212
Endometrial cancer	KEGG	ko05213
Glioma	KEGG	ko05214
Prostate cancer	KEGG	ko05215
Thyroid cancer	KEGG	ko05216
Melanoma	KEGG	ko05218
Bladder cancer	KEGG	ko05219
Chronic myeloid leukemia	KEGG	ko05220
Acute myeloid leukemia	KEGG	ko05221
Small cell lung cancer	KEGG	ko05222
Non-small cell lung cancer	KEGG	ko05223
Cell cycle	KEGG	hsa04110
p53 signaling pathway	KEGG	hsa04115
Wnt signaling pathway	KEGG	hsa04310
Hedgehog signaling pathway	KEGG	hsa04340
Focal adhesion	KEGG	hsa04510
Tight junction	KEGG	hsa04530
Jak-STAT signaling pathway	KEGG	hsa04630
Pathways in cancer	KEGG	hsa05200
Colorectal cancer	KEGG	hsa05210
Pancreatic cancer	KEGG	hsa05212
Endometrial cancer	KEGG	hsa05213
Glioma	KEGG	hsa05214
Prostate cancer	KEGG	hsa05215
Thyroid cancer	KEGG	hsa05216
Melanoma	KEGG	hsa05218
Bladder cancer	KEGG	hsa05219
Chronic myeloid leukemia	KEGG	hsa05220
Acute myeloid leukemia	KEGG	hsa05221
Small cell lung cancer	KEGG	hsa05222
Non-small cell lung cancer	KEGG	hsa05223
Viral myocarditis	KEGG	hsa05416
Measles	KEGG	ko05162
Measles	KEGG	hsa05162
HTLV-I infection	KEGG	ko05166
HTLV-I infection	KEGG	hsa05166
Viral carcinogenesis	KEGG	hsa05203
Viral carcinogenesis	KEGG	ko05203
PI3K-Akt signaling pathway	KEGG	hsa04151
PI3K-Akt signaling pathway	KEGG	ko04151
Hepatitis B	KEGG	hsa05161
Hippo signaling pathway	KEGG	hsa04390
Hippo signaling pathway	KEGG	ko04390
Proteoglycans in cancer	KEGG	hsa05205
Proteoglycans in cancer	KEGG	ko05205
Prolactin signaling pathway	KEGG	hsa04917
Prolactin signaling pathway	KEGG	ko04917
MicroRNAs in cancer	KEGG	hsa05206
MicroRNAs in cancer	KEGG	ko05206
FoxO signaling pathway	KEGG	hsa04068
Thyroid hormone signaling pathway	KEGG	hsa04919
Oxytocin signaling pathway	KEGG	hsa04921
Oxytocin signaling pathway	KEGG	ko04921
AMPK signaling pathway	KEGG	hsa04152
AMPK signaling pathway	KEGG	ko04152
Cell cycle - G1/S transition	KEGG	hsa_M00692
Cell cycle - G1/S transition	KEGG	M00692
Immune System	REACTOME	R-HSA-168256
Cytokine Signaling in Immune system	REACTOME	R-HSA-1280215
Signaling by Interleukins	REACTOME	R-HSA-449147
Signal Transduction	REACTOME	R-HSA-162582
Signaling by NOTCH	REACTOME	R-HSA-157118
Pre-NOTCH Expression and Processing	REACTOME	R-HSA-1912422
Pre-NOTCH Transcription and Translation	REACTOME	R-HSA-1912408
Cell Cycle	REACTOME	R-HSA-1640170
Cell Cycle, Mitotic	REACTOME	R-HSA-69278
Mitotic G1-G1/S phases	REACTOME	R-HSA-453279
G1 Phase	REACTOME	R-HSA-69236
Cyclin D associated events in G1	REACTOME	R-HSA-69231
G1/S Transition	REACTOME	R-HSA-69206
Cyclin E associated events during G1/S transition	REACTOME	R-HSA-69202
SCF(Skp2)-mediated degradation of p27/p21	REACTOME	R-HSA-187577
S Phase	REACTOME	R-HSA-69242
Cyclin A:Cdk2-associated events at S phase entry	REACTOME	R-HSA-69656
Ubiquitin-dependent degradation of Cyclin D	REACTOME	R-HSA-75815
Ubiquitin-dependent degradation of Cyclin D1	REACTOME	R-HSA-69229
Chromatin organization	REACTOME	R-HSA-4839726
Chromatin modifying enzymes	REACTOME	R-HSA-3247509
RMTs methylate histone arginines	REACTOME	R-HSA-3214858
AGE-RAGE signaling pathway in diabetic complications	KEGG	ko04933
AGE-RAGE signaling pathway in diabetic complications	KEGG	hsa04933
Signaling by PTK6	REACTOME	R-HSA-8848021
PTK6 Regulates Cell Cycle	REACTOME	R-HSA-8849470
Endocrine resistance	KEGG	ko01522
Endocrine resistance	KEGG	hsa01522
Breast cancer	KEGG	ko05224
Breast cancer	KEGG	hsa05224
Interleukin-4 and 13 signaling	REACTOME	R-HSA-6785807
Apelin signaling pathway	KEGG	hsa04371

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA10040	cetuximab	Chemical	ClinicalAnnotation	associated	PD	16788380, 18349392, 22117530
PA128406956	fluorouracil	Chemical	ClinicalAnnotation	associated	PD	23567490
PA152241907	lapatinib	Chemical	VariantAnnotation	associated	PD
PA443560	Breast Neoplasms	Disease	VariantAnnotation	associated	PD
PA443756	Colonic Neoplasms	Disease	ClinicalAnnotation	associated	PD	23567490
PA446108	Colorectal Neoplasms	Disease	ClinicalAnnotation	associated	PD	16788380, 18349392, 22117530
PA446155	Precursor Cell Lymphoblastic Leukemia-Lymphoma	Disease	ClinicalAnnotation	associated	PD	12972956, 16870553
PA450428	methotrexate	Chemical	ClinicalAnnotation	associated	PD	12972956, 16870553

References

Pubmed ID	Year	Title	Citations
18212742	2008	The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.	306
18710938	2008	Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells.	225
15755896	2005	Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma.	182
18406353	2008	Downregulation of CCND1 and CDK6 by miR-34a induces cell cycle arrest.	181
18695042	2008	A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation.	161
18456656	2008	The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer.	153
17081987	2006	Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex.	152
12914697	2003	A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer.	143
12067972	2002	Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma.	121
21654808	2011	A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers.	117

Citation

Shreya Sarkar ; Chinmay Kumar Panda

CCND1 (B-cell leukemia/lymphoma 1)

Atlas Genet Cytogenet Oncol Haematol. 2015-04-01

Online version: http://atlasgeneticsoncology.org/gene/36/meetings/

Historical Card

1998-05-01 CCND1 (B-cell leukemia/lymphoma 1) by Jean-Loup Huret Affiliation

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France