Search

Background Nuclear‐to‐mitochondrial communication regulating gene expression and mitochondrial function is a critical process following cardiac ischemic injury. In this study, we determined that cyclin C, a component of the Mediator complex, regulates cardiac and mitochondrial function in part by modifying mitochondrial fission. We tested the hypothesis that cyclin C functions as a transcriptional cofactor in the nucleus and a signaling molecule stimulating mitochondrial fission in response to stimuli such as cardiac ischemia. Methods and Results We utilized gain‐ and loss‐of‐function mouse models in which the CCNC (cyclin C) gene was constitutively expressed (transgenic, CycC cTg) or deleted (knockout, CycC cKO) in cardiomyocytes. The knockout and transgenic mice exhibited decreased cardiac function and altered mitochondria morphology. The hearts of knockout mice had enlarged mitochondria with increased length and area, whereas mitochondria from the hearts of transgenic mice were significantly smaller, demonstrating a role for cyclin C in regulating mitochondrial dynamics in vivo. Hearts from knockout mice displayed altered gene transcription and metabolic function, suggesting that cyclin C is essential for maintaining normal cardiac function. In vitro and in vivo studies revealed that cyclin C translocates to the cytoplasm, enhancing mitochondria fission following stress. We demonstrated that cyclin C interacts with Cdk1 (cyclin‐dependent kinase 1) in vivo following ischemia/reperfusion injury and that, consequently, pretreatment with a Cdk1 inhibitor results in reduced mitochondrial fission. This finding suggests a potential therapeutic target to regulate mitochondrial dynamics in response to stress. Conclusions Our study revealed that cyclin C acts as a nuclear‐to‐mitochondrial signaling factor that regulates both cardiac hypertrophic gene expression and mitochondrial fission. This finding provides new insights into the regulation of cardiac energy metabolism following acute ischemic injury.

During development of the vertebrate CNS, the basic helix-loop-helix (bHLH) transcription factor Olig2 sustains replication competence of progenitor cells that give rise to neurons and oligodendrocytes. A pathological counterpart of this developmental function is seen in human glioma, wherein Olig2 is required for maintenance of stem-like cells that drive tumor growth. The mitogenic/gliomagenic functions of Olig2 are regulated by phosphorylation of a triple serine motif (S10, S13, and S14) in the amino terminus. Here, we identify a set of three serine/threonine protein kinases (glycogen synthase kinase 3α/β [GSK3α/β], casein kinase 2 [CK2], and cyclin-dependent kinases 1/2 [CDK1/2]) that are, collectively, both necessary and sufficient to phosphorylate the triple serine motif. We show that phosphorylation of the motif itself serves as a template to prime phosphorylation of additional serines and creates a highly charged "acid blob" in the amino terminus of Olig2. Finally, we show that small molecule inhibitors of this forward-feeding phosphorylation cascade have potential as glioma therapeutics.

In this issue of Genes & Development, Besson et al. (2007) report phenotypic characteristics of a novel knock-in mouse strain expressing a mutant allele of the cell cycle inhibitor p27 KiP1 that has both common and unique features when compared with a null allele. The new studies provide the first direct in vivo evidence that in addition to its role as a tumor suppressor, p27 Kip1 also functions as an oncogene. The work also suggests that p27 Kip1 oncogenic activity leads to aberrant stem and progenitor cell expansion in the lung and retina, respectively. Thus, p27 KiP1 's new "dark side" may serve an oncogenic function that operates in less specialized cell types to influence tumorigenesis. creased patient survival (Slingerland and Pagano 2000). Germline mutation of p27 Kip1 was also recently described in a subset of MEN (Multiple Endocrine Neoplasia) syndrome patients in humans, as well as in rats with the related MENX syndrome (Pellegata et al. 2006). p27 Kip1 -null mice develop organomegaly and pituitary adenomas (Fero et al. 1996; Kiyokawa et al. 1996; Nakayama et al. 1996). The most simplistic explanation of the phenotypes was that in p27 Kip1-/- mice, the deregulated CDK2 kinase was responsible for these symptoms. However, recent observations that ablation of CDK2 in p27 Kip1 -null background did not mitigate the phenotypes of p27 Kip1 deficiency clearly shows that p27 Kip1 can act independently of CDK2, likely in part by hyperactivating CDK1 (Aleem et al. 2005; Martin et al. 2005).

Mutations in DNA repair genes show peculiar defects in central nervous system morphogenesis characterized by dramatic cerebellar dysmorphia with relatively preserved forebrain development. Loss of ...

A fundamental aspect of cancer is dysregulated cell cycle control. Unlike normal cells that only proliferate when compelled to do so by developmental or other mitogenic signals in response to tissue growth needs, the proliferation of cancer cells proceeds essentially unchecked. This does not mean that cancer cell cycles are necessarily different from those found in normal cycling cells, but rather implies that cancer cells proliferate because they are no longer subject to proliferation-inhibitory influences arising from the stroma or from gene expression pattern changes consequent to 'terminal' differentiation, nor do they necessarily require extrinsic growth factors to recruit them into or maintain their proliferative state. Finally, cancer cells have also often avoided normal controls linked to cell cycle progression that halt proliferation in the presence of damaged DNA or other physiological insults. The result of these alterations is the inappropriate proliferation commonly associated with cancerous tumor formation. This review will summarize the current understanding of dysregulation of the G0/G1-to-S-phase transition in cancer cells, with particular emphasis on recent in vivo studies that suggest a need to rethink existing models of cell cycle control in development and tumorigenesis.

Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPARδ induces cell proliferation through a novel cyclin E1–dependent mechanism and is up-regulated in many human thyroid tumors. The expression of PPARδ was induced coordinately with proliferation in primary human thyroid cells by the activation of serum, thyroid-stimulating hormone/cyclic AMP, or epidermal growth factor/mitogen-activated protein kinase mitogenic signaling pathways. Engineered overexpression of PPARδ increased thyroid cell number, the incorporation of bromodeoxyuridine, and the phosphorylation of retinoblastoma protein by 40% to 45% in just 2 days, one usual cell population doubling. The synthetic PPARδ agonist GW501516 augmented these PPARδ proliferation effects in a dose-dependent manner. Overexpression of PPARδ increased cyclin E1 protein by 9-fold, whereas knockdown of PPARδ by small inhibitory RNA reduced both cyclin E1 protein and cell proliferation by 2-fold. Induction of proliferation by PPARδ was abrogated by knockdown of cyclin E1 by small inhibitory RNA in primary thyroid cells and by knockout of cyclin E1 in mouse embryo fibroblasts, confirming a cyclin E1 dependence for this PPARδ pathway. In addition, the mean expression of native PPARδ was increased by 2-fold to 5-fold (P < 0.0001) and correlated with that of the in situ proliferation marker Ki67 (R = 0.8571; P = 0.02381) in six different classes of benign and malignant human thyroid tumors. Our experiments identify a PPARδ mechanism that induces cell proliferation through cyclin E1 and is regulated by growth factor and lipid signals. The data argue for systematic investigation of PPARδ antagonists as antineoplastic agents and implicate altered PPARδ–cyclin E1 signaling in thyroid and other carcinomas. [Cancer Res 2008;68(16):6578–86]

Mice likely represent the most-studied mammalian organism, except for humans. Genetic engineering in embryonic stem cells has allowed derivation of mouse strains lacking particular cell cycle proteins. Analyses of these mutant mice, and cells derived from them, facilitated the studies of the functions of cell cycle apparatus at the organismal and cellular levels. In this review, we give some background about the cell cycle progression during mouse development. We next discuss some insights about in vivo functions of the cell cycle proteins, gleaned from mouse knockout experiments. Our text is meant to provide examples of the recent experiments, rather than to supply an extensive and complete list.