Cyclin E in normal physiology and disease states

Abstract

E-type cyclins, collectively called cyclin E, represent key components of the core cell cycle machinery. In mammalian cells, two E-type cyclins, E1 and E2, activate cyclin-dependent kinase 2 (CDK2) and drive cell cycle progression by phosphorylating several cellular proteins. Abnormally elevated activity of cyclin E-CDK2 has been documented in many human tumor types. Moreover, cyclin E overexpression mediates resistance of tumor cells to various therapeutic agents. Recent work has revealed that the role of cyclin E extends well beyond cell proliferation and tumorigenesis, and it may regulate a diverse array of physiological and pathological processes. In this review, we discuss these various cyclin E functions and the potential for therapeutic targeting of cyclin E and cyclin E-CDK2 kinase.

Keywords: CDK2; cancer; cell cycle; cyclin E; cyclin-dependent kinases.

Figure 1.. Overview of Cyclin E Physiological Functions.

Cyclin E exerts its physiological functions through cell cycle kinases (mainly CDK2). Cyclin E binds and activates CDK2, which then phosphorylates a range of substrates involved in different physiological functions such as cell cycle progression, male meiosis, and stem cell maintenance. Cyclin E also binds to CDK5 and sequesters it from its activating partners p35 and p39, and therefore negatively regulates its activity. This mechanism was shown to affect the synaptic functions in the brain. Cyclin E can also bind to CDK1 or CDK3, but the physiological significance and molecular functions of these complexes remain unknown. Lastly, cyclin E also plays kinase-independent functions, such as to facilitate loading of MCMs onto chromatin during G0 – S phase progression, and loading of MCM5 to the centrosomes during centrosome duplication. Abbreviations: E1, cyclin E1; E2, cyclin E2. Wave1, Wiskott-Aldrich syndrome protein family verprolin homologous protein 1, which together with Synapsin I represents synaptic CDK5 substrates. CP110, centriolar coiled-coil protein 110. Histone-lysine N-methyltransferase Ehmt1 represents a Nrf1 transcriptional target.

Figure 2.. Overview of Cyclin E Deregulation Mechanisms and Its Functions in Cancer.

Cyclin E is frequently deregulated in cancer. Different mechanisms include amplification of cyclin E genes, abnormal upregulation of its expression by different factors, the loss or decreased activity of its turnover machinery, or downregulation of CDK2 inhibitors. Deregulated cyclin E hyperactivates CDK2, thereby affecting a variety of its downstream substrates. Cyclin E overexpression causes S-phase and mitotic defects which lead to genome instability in cancer cells. It also mediates resistance to a number of therapeutic reagents. The cancer-specific low-molecular-weight cyclin E can regulate cytoplasmic proteins such as ACLY, and can phosphorylate nuclear substrates, such as histone-acetyltransferase HBO1. Abbreviations: LMW-E, low-molecular-weight cyclin E; AR, androgen receptor; MCM, minichromosome maintenance complex; MSLN, mesothelin, which upregulates cyclin E1 expression via phosphorylated Stat3 (pStat3); ACLY, ATP-citrate lysase.

Figure 3.. Targeting Cyclin E-CDK2 in Cancer.

Inhibition of CDK2, the major catalytic partner of cyclin E, can lead to a variety of therapeutically beneficial outcomes, such as halting cancer cell proliferation, causing cell death, and re-sensitizing resistant cells to therapeutic reagents. Dashed lines indicate that in KRAS-mutant lung cancer cells, activated KRAS was shown to decrease CP110 protein level. Abbreviations: CP110, centriolar coiled-coil protein 110; BRCA1, breast cancer type 1 susceptibility protein; ATM, ATM serine/threonine kinase; KRAS, KRAS proto-oncogene, GTPase; AML, acute myeloid leukemia.

Figure I.. Mouse Models for Studies of Cyclin E in Cancer.

Several cyclin E ‘gain-of-function’ (A) and ‘loss-of-function’ (B) models have been developed to study the function of cyclin E in cancer. Abbreviations: LMW-E, low-molecular-weight cyclin E; E1, cyclin E1; E2, cyclin E2; hE1, human cyclin E1; NMU, carcinogen N-methylnitrosourea; MEF, mouse embryonic fibroblasts.