CCND1
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Cyclin D1 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''CCND1''
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.


Gene expression

The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs long, and translates into 295 amino acids. Cyclin D1 is expressed in all adult human tissues with the exception of cells derived from bone marrow stem cell lines (both lymphoid and myeloid).


Protein structure

Cyclin D1 is composed of the following protein domains and motifs: * retinoblastoma protein (pRb) binding motif; * cyclin box domain for cyclin-dependent kinase (CDK) binding and CDK inhibitor binding; * LxxLL binding motif for co-activator recruitment; * PEST sequence that may mark the protein for degradation; * threonine residue (threonine 286) that controls nuclear export and protein stability.


Function

The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDKs ( Cyclin-dependent kinase). Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or
CDK6 Cell division protein kinase 6 (CDK6) is an enzyme encoded by the ''CDK6'' gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of th ...
, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis. Immunohistochemical staining of cyclin D1 antibodies is used to diagnose
mantle cell lymphoma Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph n ...
. Cyclin D1 has been found to be overexpressed in
breast carcinoma Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a ...
. Its potential use as a biomarker was suggested.


Normal function

Cyclin D1 was originally cloned as a breakpoint rearrangement in parathyroid adenoma and was shown to be required for progression through the G1 phase of the cell cycle to induce cell migration, angiogenesis and to induce the Warburg effect. Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle. During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase. Cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6. The protein dimerizes with CDK4/6 to regulate the G1/S phase transition and entry into the S-phase.


CDK dependent functions

The cyclin D1-CDK4 complex promotes passage through the G1 phase by inhibiting the retinoblastoma protein (pRb). Cyclin D1-CDK4 inhibits pRb through phosphorylation, allowing E2F transcription factors to transcribe genes required for entry into the S phase. Inactive pRb allows cell cycle progression through the G1/S transition and allows for DNA synthesis. Cyclin D1-CDK4 also enables the activation of cyclin E-CDK2 complex by sequestering Cip/Kip family CDK inhibitory proteins p21 and p27, allowing entry into the S phase. Cyclin D1-CDK4 also associates with several transcription factors and transcriptional co-regulators.


CDK independent functions

Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α, thyroid hormone receptor, PPARγ and AR ) to regulate cell proliferation, growth, and differentiation. Cyclin D1 also binds to histone acetylases and histone deacetylases to regulate cell proliferation and cell differentiation genes in the early to mid-G1 phase.


Synthesis and degradation

Increasing cyclin D1 levels during the G1 phase is induced by mitogenic growth factors primarily through Ras-mediated pathways, and hormones. These Ras-mediated pathways lead to the increase in transcription of cyclin D1, and inhibit its proteolysis and export from the nucleus. Cyclin D1 is degraded by the proteasome upon phosphorylation of threonine 286 and subsequent
ubiquitylation Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fou ...
via the CRL4-AMBRA1 E3 ubiquitin ligase complex.


Clinical significance


Deregulation in cancer

Cyclin D1 overexpression has been shown to correlate with early cancer onset and tumor progression and it can lead to oncogenesis by increasing anchorage-independent growth and angiogenesis via VEGF production. Cyclin D1 overexpression can also down-regulate Fas expression, leading to increased chemotherapeutic resistance and protection from apoptosis. An abundance of cyclin D1 can be caused by various types of deregulation, including: * amplification of the CCND1 gene / overexpression of cyclin D1; * chromosomal translocation of the CCND1 gene; *mutations in the degradation motif recognized by the CRL4-AMBRA1 E3 ubiquitin ligase; * disruption of nuclear export and proteolysis of cyclin D1; *induction of transcription by oncogenic Ras, Src, ErbB2 and STATs; Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis. Amplification of the CCND1 gene is present in: * non-small cell lung cancers (30-46%) * head and neck squamous cell carcinomas (30-50%) * pancreatic carcinomas (25%) * bladder cancer (15%) * pituitary adenomas (49-54%) * breast carcinoma (13%) Cyclin D1 overexpression is strongly correlated to ER+ breast cancer and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer. Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers. Chromosomal translocation around the cyclin D1 gene locus is often seen in B mantle cell lymphoma. In mantle cell lymphoma, cyclin D1 is translocated to the IgH promoter leading to cyclin D1 overexpression. Chromosomal translocation of the cyclin D1 gene locus is also observed in 15 – 20% of multiple myelomas.


Therapeutic target in cancer

Cyclin D1 and the mechanisms it regulates have the potential to be a therapeutic target for cancer drugs:


Interactions

Cyclin D1 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: * NR3C4, *
BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
, *
CCNDBP1 Cyclin-D1-binding protein 1 is a protein that in humans is encoded by the ''CCNDBP1'' gene. This gene was identified by the interaction of its gene product with Grap2, a leukocyte-specific adaptor protein important for immune cell signaling. The ...
, * CDK4, *
CDK6 Cell division protein kinase 6 (CDK6) is an enzyme encoded by the ''CDK6'' gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of th ...
, *
ESR1 Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex ...
* HDAC3, * HDACs *
NEUROD1 Neurogenic differentiation 1 (Neurod1), also called β2, is a transcription factor of the NeuroD-type. It is encoded by the human gene NEUROD1. In mice, ''Neurod1'' expression is first seen at embryonic day 12 (E12). It is a member of the Neurod ...
, *
NCOA1 The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ...
, *
NRF1 Nuclear respiratory factor 1, also known as Nrf1, Nrf-1, NRF1 and NRF-1, encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nucl ...
, * p300, *
PACSIN2 Protein kinase C and casein kinase substrate in neurons protein 2 (Pacsin 2) is a protein that in humans is encoded by the ''PACSIN2'' gene. Pacsin 2 is involved in the formation of caveolae In biology, caveolae ( Latin for "little caves"; singula ...
, *
PCNA Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells and is essential for replication. PCNA is a homotrimer and achieves its processivity by encircling the DNA, wh ...
, *
PPARG Peroxisome proliferator- activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a tran ...
, * RAD51, * RB1, *
TAF1 Transcription initiation factor TFIID subunit 1, also known as transcription initiation factor TFIID 250 kDa subunit (TAFII-250) or TBP-associated factor 250 kDa (p250), is a protein that in humans is encoded by the ''TAF1'' gene. Function Init ...
, and * NR1A2.


See also

*
Parathyroid adenoma A parathyroid adenoma is a benign tumor of the parathyroid gland. It generally causes hyperparathyroidism; there are very few reports of parathyroid adenomas that were not associated with hyperparathyroidism. A human being usually has four parath ...
*
Mantle Cell Lymphoma Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph n ...


References


Further reading

* * * * * * * * * * * * * * * * * * * {{Cell cycle proteins