Cell Cycle and Cancer: Focus on Cyclin D1 and CDKs

The Cell Cycle

Overview of Cyclin Dependent Kinases (CDKs)

  • Cyclins that Activate CDKs:

    • Cyclin A (1,2)

    • Cyclin B (1,2)

    • Cyclin D (1,2,3)

    • Cyclin E (1,2)

Cyclin D Family

  • Cyclin levels fluctuate during the cell cycle, while CDK levels are generally constant, but their activity varies depending on the presence of specific cyclins.

  • CDK activity is controlled by activating partners.

The Mammalian CDK Family

  • Characterization:

    • Small serine/threonine kinases.

    • Monomers are inactive; activation occurs upon binding to regulatory partners.

    • They bind ATP and phosphorylate substrates when active.

    • More than 20 CDKs in humans, sharing at least 40% homology.

    • Regulated by phosphorylation/dephosphorylation and small inhibitors.

  • Important Note: A cyclin cannot phosphorylate a substrate directly.

Description and Characteristics of Cyclins

  • Modifications include lengths (amino acids count):

    • Cyclin A1: 465 aa

    • Cyclin D1: 295 aa

    • Cyclin D2: 289 aa

    • Cyclin E1: 410 aa

  • Specific cyclin features: N-terminal/binding boxes, Ubiquitin-like signals, Nuclear localization signals, Proline-rich stretches.

CDKs and Cancer Progression

  • CDK inhibitors are currently used in cancer treatment, specifically CDK4/6 inhibitors for breast cancer and lung cancer.

  • Data suggests that CDK4 and CDK6 are implicated in various cancer types due to their roles in cell cycle regulation.

Cyclin D1 and Cancer

  • Cyclin D1 is crucial in cell transformation and progression in various tumor types, with gene amplification often indicating poor prognosis.

  • Studies reveal elevated cyclin D1 levels in cancers linked with increased gene expression due to gene amplification, RNA stability, and altered localization.

Mechanisms of Cyclin D1 Upregulation

  1. Gene Amplification:

    • Southern blotting is used to examine gene copy number, observing amplification of CCND1 in various tumors.

  2. Increased mRNA Stability:

    • Northern blotting methods assess mRNA levels, with some tumors showing elevated cyclin D1 mRNA due to altered 3' UTR sequences.

  3. Altered Subcellular Localization:

    • Elevated nuclear accumulation of cyclin D1 has been linked to cancer transformation.

Specific Conditions Associated with Cyclin D1

  • Mantle Cell Lymphoma (MCL):

    • Characterized by chromosomal translocations leading to cyclin D1 overexpression, contributing to deregulation of the cell cycle.

    • Poor prognosis associated with this form of cancer (median survival 3-4 years).

    • Cyclin D1 is significantly overexpressed and linked with aggressive disease progression.

Other Cancer Types

  • Endometrial Carcinoma:

    • Increased incidence, linked to obesity and type-2 diabetes.

  • Survival disparities based on ethnicity observed in studies on endometrial cancer outcomes.

Therapeutics and Targeting CDKs

  • Specific inhibitors designed to block the interaction of CDK4/6 with cyclin D1 can prevent activation of pRB and subsequent G1 to S phase progression.

  • CDK4/6 inhibitors approved by the FDA for treating ER+/HER2- breast cancer patients.

Conclusion

  • Cyclin D1's role in cell cycle regulation indicates a dual function dependent on CDK activity:

    • CDK-dependent: Phosphorylation of pRB and regulation of cell cycle checkpoints.

    • CDK-independent: Sequestration of negative regulators and direct gene expression regulation.

Learning Objectives

  • Understanding the regulation of the cell cycle, especially in G1/S phase transitions.

  • Using cyclin D1 as a case study in oncogene research and therapeutic development.