Cyclin D1

Cyclin D1 was originally cloned as a breakpoint rearrangement in parathyroid adenoma[5] and was shown to be required for progression through the G1 phase of the cell cycle to induce cell migration,[14] angiogenesis[15] and to induce the Warburg effect.[16] Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle.[17] During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase.[17] 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.

The cyclin D1-CDK4 complex promotes passage through the G1 phase by inhibiting the retinoblastoma protein (pRb).[18] 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.[19]

Cyclin D1-CDK4 also associates with several transcription factors and transcriptional co-regulators.[10]

Independent of CDK, cyclin D1 binds to nuclear receptors (including estrogen receptor α,[20] thyroid hormone receptor, PPARγ[21][22] and AR[23] ) 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 [24][25][23][26] in the early to mid-G1 phase.

Cyclin D1 overexpression has been shown to correlate with early cancer onset and tumor progression [19] and it can lead to oncogenesis by increasing anchorage-independent growth and angiogenesis via VEGF production.[33] Cyclin D1 overexpression can also down-regulate Fas expression, leading to increased chemotherapeutic resistance and protection from apoptosis.[33]

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;[32]
• disruption of nuclear export[34] and proteolysis of cyclin D1;[35]
• induction of transcription by oncogenic Ras, Src, ErbB2 and STATs;[36][37][38][39]

Cyclin D1 overexpression is correlated with shorter cancer patient survival and increased metastasis.[40][41] Amplification of the CCND1 gene is present in:

• non-small cell lung cancers (30–46%)[42][43]
• head and neck squamous cell carcinomas (30–50%)[44][45][46]
• pancreatic carcinomas (25%)[47]
• bladder cancer (15%)[48]
• pituitary adenomas (49–54%) [49][50]
• breast carcinoma (13%)[51][52][53]

Cyclin D1 overexpression is strongly correlated to ER+ breast cancer[53] and deregulation of cyclin D1 is associated with hormone therapy resistance in breast cancer.[32][54][55] Overexpression of Cyclin D1b, an isoform, is also present in breast and prostate cancers.[11]

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[56] leading to cyclin D1 overexpression. Chromosomal translocation of the cyclin D1 gene locus is also observed in 15–20% of multiple myelomas.[57][58]

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