Cyclin E is a protein that regulates various cellular processes. It belongs to the cyclin family, which controls cell growth and division. Its proper functioning is important for maintaining normal cell behavior and overall bodily health.
Cyclin E’s Role in Cell Division
Cell division is a highly organized process that occurs in distinct stages: G1 (Gap 1), S (Synthesis), G2 (Gap 2), and M (Mitosis). During the G1 phase, the cell grows and prepares for DNA replication. The S phase is when DNA synthesis occurs, resulting in two identical sets of chromosomes. Following this, the cell enters G2, preparing for cell division, which then culminates in the M phase where the cell divides into two daughter cells.
Cyclin E plays a specific role in the transition from the G1 phase to the S phase, acting as a “gatekeeper” for DNA synthesis. To move from G1 into S phase, cyclin E partners with Cyclin-Dependent Kinase 2 (CDK2), forming an active complex. This cyclin E/CDK2 complex then phosphorylates, or adds a phosphate group to, proteins like the retinoblastoma protein (Rb).
Phosphorylation of Rb by the cyclin E/CDK2 complex inactivates Rb, allowing the release of transcription factors like E2F. These E2F factors activate genes necessary for DNA replication and cell progression into the S phase. Without sufficient cyclin E activity, the cell’s entry into DNA synthesis would be inhibited, ensuring DNA replication occurs only when appropriate.
Controlling Cyclin E Activity
The body maintains tight control over cyclin E levels and activity to ensure proper cell function and prevent uncontrolled growth. Cyclin E’s presence peaks at the G1 to S phase transition, and its levels are regulated through production and controlled removal. This control is achieved through ubiquitin-mediated proteolysis, involving the ubiquitin-proteasome system.
The ubiquitin-proteasome system degrades unwanted or excess proteins. Ubiquitin, a small protein, attaches to cyclin E, tagging it for degradation by the proteasome. Free cyclin E, not bound to CDK2, is readily ubiquitinated and degraded, keeping its levels low when not needed.
When cyclin E is bound to CDK2, it is protected from ubiquitination. However, CDK2 activity can reverse this protection by phosphorylating cyclin E, triggering its ubiquitination and degradation by the proteasome. This ensures cyclin E is active for a limited time, preventing accumulation and maintaining proper cell cycle progression. The regular rise and fall of cyclin E levels are important for healthy cell function, ensuring cell division proceeds in an orderly and controlled manner.
Cyclin E and Disease
Dysregulation of cyclin E, such as overexpression or impaired degradation, is strongly linked to cancer development. Abnormally high levels or improper degradation of cyclin E can lead to uncontrolled cell division. This uncontrolled growth is a hallmark of many cancers.
Elevated cyclin E levels are observed in various types of human cancers, including breast, ovarian, and endometrial cancers. For instance, cyclin E gene amplification is found in approximately 22% of ovarian cancers, 18% of esophageal/gastric cancers, and 14% of endometrial cancers. In breast cancer, increased cyclin E expression is found in 18% to 22% of cases and is associated with more aggressive tumor characteristics and shorter survival.
Low molecular weight isoforms of cyclin E are observed in breast cancer and are associated with a poor prognosis. Overexpression of cyclin E can also contribute to chemotherapy resistance, making treatments less effective. Because of its involvement in cell proliferation and its presence in various malignancies, cyclin E is being investigated as a potential prognostic marker and a target for future cancer therapies.