Emerging role of DYRK family protein kinases as regulators of protein stability in cell cycle control

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family phosphorylate many substrates, including critical regulators of the cell cycle. A recent report revealed that human DYRK2 acts as a negative regulator of G₁/S transition by phosphorylating c-Jun and c-Myc, thereby inducing ubiquitination-mediated degradation. Other DYRKs also function as cell cycle regulators by modulating the turnover of their target proteins. DYRK1B can induce reversible cell arrest in a quiescent G₀ state by targeting cyclin D1 for proteasomal degradation and stabilizing p27^Kip1. The DYRK2 ortholog of C. elegans, MBK-2, triggers the proteasomal destruction of oocyte proteins after meiosis to allow the mitotic divisions in embryo development. This review summarizes the accumulating results that provide evidence for a general role of DYRKs in the regulation of protein stability.     

Emerging role of DYRK family protein kinases as regulators of protein stability in cell cycle control

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family phosphorylate many substrates, including critical regulators of the cell cycle. A recent report revealed that human DYRK2 acts as a negative regulator of G₁/S transition by phosphorylating c-Jun and c-Myc, thereby inducing ubiquitination-mediated degradation. Other DYRKs also function as cell cycle regulators by modulating the turnover of their target proteins. DYRK1B can induce reversible cell arrest in a quiescent G₀ state by targeting cyclin D1 for proteasomal degradation and stabilizing p27^Kip1. The DYRK2 ortholog of C. elegans, MBK-2, triggers the proteasomal destruction of oocyte proteins after meiosis to allow the mitotic divisions in embryo development. This review summarizes the accumulating results that provide evidence for a general role of DYRKs in the regulation of protein stability.     

Cell cycle regulators in the control of metabolism

We recently showed that the CDK4-pRB-E2F1 cell cycle regulators directly regulate the expression of Kir6.2, which is a key component of the K_ATP channel involved in the regulation of glucose-induced insulin secretion. There is enough evidence to indicate that the CDK4-pRB-E2F1 regulatory pathway is involved in general glucose homeostasis, and metabolism. In this article we discuss which are the metabolic implications of these findings.     

Role of cell cycle regulators in lung carcinogenesis

Cellular division is an ordered, tightly regulated process involving multiple checkpoints that assess extracellular growth signals, cell size, and DNA integrity. Progression throughout the cell cycle is based on the activation of different CDK-cyclin complexes that prevent cells from entering into a new phase until thay have successfully complete the previous one. In addition, a series of cell cycle checkpoints are designed to preserve genome integrity and chromosomal stability. Neoplastic lung cells develop the ability to bypass several of these checkpoints, and tumor cell proliferation is frequently associated with genetic or epigenetic alterations in key regulators of the cell cycle. The goal of this review is to summarize the knowledge about the dysregulation of major cell-cycle regulators in lung cancer pathogenesis, and to discuss the use of these proteins as targets for therapeutic intervention.     

The cell cycle and development: redundant roles of cell cycle regulators

The existence of families of cell cycle regulators reflects the need by a developing organism to precisely control proliferation of its cells and also suggests that family members may play redundant roles. Recent advances have shown redundancy to be a theme in development.     

Promiscuous and lineage-specific roles of cell cycle regulators in haematopoiesis

DNA double strand breaks are efficiently repaired by homologous recombination. One of the last steps of this process is resolution of Holliday junctions that are formed at the sites of genetic exchange between homologous DNA. Although various resolvases with Holliday junctions processing activity have been identified in bacteriophages, bacteria and archaebacteria, eukaryotic resolvases have been elusive. Recent biochemical evidence has revealed that RAD51C and XRCC3, members of the RAD51-like protein family, are involved in Holliday junction resolution in mammalian cells. However, purified recombinant RAD51C and XRCC3 proteins have not shown any Holliday junction resolution activity. In addition, these proteins did not reveal the presence of a nuclease domain, which raises doubts about their ability to function as a resolvase. Furthermore, oocytes from infertile Rad51C mutant mice exhibit precocious separation of sister chromatids at metaphase II, a phenotype that reflects a defect in sister chromatid cohesion, not a lack of Holliday junction resolution. Here we discuss a model to explain how a Holliday junction resolution defect can lead to sister chromatid separation in mouse oocytes. We also describe other recent in vitro and in vivo evidence supporting a late role for RAD51C in homologous recombination in mammalian cells, which is likely to be resolution of the Holliday junction.     

Effect of HIV-1 Vpr on cell cycle regulators

Cell cycle is one of the most complex processes in the life of a dividing cell. It involves numerous regulatory proteins, which direct the cell through a specific sequence of events for the production of two daughter cells. Cyclin-dependent kinases (cdks), which complex with the cyclin proteins, are the main players in the cell cycle. They can regulate the progression of the cells through different stages regulated by several proteins including p53, p21(WAF1), p19, p16, and cdc25. Downstream targets of cyclin-cdk complexes include pRB and E2F. A cell cycle can be altered to the advantage of many viral agents, most notably polyomaviruses, papillomaviruses, adenoviruses, and retroviruses. In addition, viral protein R (Vpr) is a protein encoded by the human immunodeficiency virus type 1 (HIV-1). HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), is a member of the lentivirus class of retroviruses. This accessory protein plays an important role in the regulation of the cell cycle by causing G(2) arrest and affecting cell cycle regulators. Vpr prevents infected cells from proliferating, and collaborates with the matrix protein (MA) to enable HIV-1 to enter the nucleus of nondividing cells. Studies from different labs including ours showed that Vpr affects the functions of cell cycle proteins, including p53 and p21(WAF1). Thus, the replication of HIV-1, and ultimately its pathogenesis, are intrinsically tied to cell-cycle control.     

RNA interference pinpoints regulators of cell size and the cell cycle

Cell-based genome-wide RNA interference screens are being used to address an increasingly broad spectrum of biological questions. In one recent screen, Drosophila cell cultures treated with double-stranded RNA were analyzed by flow cytometry, providing a wealth of new information and identifying 488 regulators of the cell cycle, cell size, and cell death.     

PRL modulates cell cycle regulators in mammary tumor epithelial cells.

PRL is essential for normal lobulo-alveolar growth of the mammary gland and may contribute to mammary cancer development or progression. However, analysis of the mechanism of action of PRL in these processes is complicated by the production of PRL within mammary epithelia. To examine PRL actions in a mammary cell-specific context, we selected MCF-7 cells that lacked endogenous PRL synthesis, using PRL stimulation of interferon-gamma-activated sequence-related PRL response elements. Derived clones exhibited a greater proliferative response to PRL than control cells. To understand the mechanism, we examined, by Western analysis, levels of proteins essential for cell cycle progression as well as phosphorylation of retinoblastoma protein. The expression of cyclin D1, a critical regulator of the G1/S transition, was significantly increased by PRL and was associated with hyperphosphorylation of retinoblastoma protein at Ser(780). Cyclin B1 was also increased by PRL. In contrast, PRL decreased the Cip/Kip family inhibitor, p21, but not p16 or p27. These studies demonstrate that PRL can stimulate the cell cycle in mammary epithelia and identify specific targets in this process. This model system will enable further molecular dissection of the pathways involved in PRL-induced proliferation, increasing our understanding of this hormone and its interactions with other factors in normal and pathogenic processes.     

Signalling molecules,growth regulators and cell cycle control in Drosophila

During the development of a given organ or tissue within a multicellular organism, growth and patterning are controlled in a coordinated manner by the activity of a discrete number of signalling molecules and their corresponding pathways to give rise to a well formed structure with a particular size, shape and pattern. Understanding how cells of different tissues or organs translate in a context dependent manner the activity of these pathways into an activation or repression of the cell cycle machinery is one of the most intriguing questions in developmental and cancer biology nowadays. Here we revise the different roles of the signalling molecules Notch and Wingless in the regulation of cell cycle progression in the developing eye and wing imaginal discs of Drosophila and propose that depending on how growth regulators are regulated in a context dependent manner by the activity of these pathways, signalling molecules might have tumour suppressor or oncogene activity.     

Cyclin-dependent protein kinases: Key regulators of the eukaryotic cell cycle

Passage through the cell cycle requires the successive activation of different cyclin-dependent protein kinases (CDKs). These enzymes are controlled by transient associations with cyclin regulatory subunits, binding of inhibitory polypeptides and reversible phosphorylation reactions. To promote progression towards DNA replication, CDK/cyclin complexes phosphorylate proteins required for the activation of genes involved in DNA synthesis, as well as components of the DNA replication machinery. Subsequently, a different set of CDK/cyclin complexes triggers the phosphorylation of numerous proteins to promote the profound structural reorganizations that accompany the entry of cells into mitosis. At present, much research is focused on elucidating the links between CDK/cyclin complexes and signal transduction pathways controlling cell growth, differentiation and death. In future, a better understanding of the cell cycle machinery and its deregulation during oncogenesis may provide novel opportunities for the diagnostic and therapeutic management of cancer and other proliferation-related diseases.