Nuclear Cyclin D1: An Oncogenic Driver in Human Cancer

JONG KYONG KIM AND J. ALAN DIEHL*

Kim su-hyun2010020727

Introduction

• Cyclin D1 is frequently overexpressed in cancers.• its overexpression can be attributed to many fact

ors including increased transcription, translation, and protein stability.

• This review provides a brief overview of cyclin D1 regulation in human cancers and their impact on neoplastic transformation.

Cell cycle regulator ; Cyclin -CDK

• The cyclin-cdks are master regulators of cell proliferation.

• These serine/theronine kinase are the motors that both start and stop the cell cycle in respose to proliferative or antiproliferative signals.

• Among which the main players in animal cells include cyclins, CDKs(cyclin-depandent kinase, positive regulator) and CDK inhibitors(negative regulators such as p21cip1 and p27kip1).

Cell-cycle regulation. WormBook. 2005

Cyclin D

• Cyclin Ds are key regulators during the G1 phase.

• There are three types of cyclin Ds, D1, D2 and D3 in mammalian cells.

• Associated cyclin-dependent kinases CDK4 and CDK6

Yew et al., 2001

D-Cyclins : Mediators of Mitogenic Signals to Core Cell Cycle Machinery

• Mitogen-dependent cyclin D1 regulation is more advanced than that for cyclin D2 and D3.

• Cyclin D1 expression and accumulation are induced by growth factors and occur at multiple levels including increased transcription, translation, and protein stability.

Cook et al. Genome Biology 2001 2:research0012.1

• Various types of cancer, including mantle cell lymphoma (MCL), non-small cell lung cancer, and carcinomas of breast, head and neck, esophagus.

• Cyclin D1 overexpression in human tumors is driven by multiple mechanisms comprising genomic alterations, posttranscriptional regulation, and post-translational protein stabilization.

D-Cyclin Overexpression in Human Cancer

• Genomic alterations: chromosomal translocations, gene amplification, and polymorphisms

• Post-transcriptional mechanisms: a target of microRNA action

• Post-translational mechanisms: perturbed nuclear export and proteolysis

D-Cyclin Overexpression in Human Cancer

Fig. 1. Cyclin D1 regulation in normal versus cancer cells.

Aberrant Nuclear Accumulation of the Cyclin D1/CDK4 Kinase and Neoplastic Transformation• Overexpression of cyclin D has been shown

to contract the G1 phase, decrease cell size, and reduce the dependency of the cell on mitogens in animal models and cell lines.

Genomic Instability in Tumors Harboring a Nuclear Cyclin D1/CDK4 Kinase

• Cyclin D1/CDK4 kinase is likely to participate more directly in the neoplastic process.

• Nuclear accumulation of catalytically active mutant cyclin D1/CDK4 complex stabilizes Cdt1, As a result, stabilized Cdt1 continually primes DNA re-replication during S phase and induces genomic instability characterized by aneuploidy.

Fig. 1. Cyclin D1 regulation in normal versus cancer cells.

Targeting Cyclin D/CDK Activity as aTherapeutic Modality• Recent studies have reported that GSK-3b

regulates proteosomal degradation of cyclin D1 protein and overexpression of cyclin D1 results from loss of GSK-3b activity.

Summary

• Individual cyclin-dependent kinases that are activated during distinct cell cycle phases.

• Cyclin D1 overexpression in human tumors is driven by multiple mechanisms.

• The contributions of cyclin D1 in human neoplasms.