Key Role In Cell Cycle Progression Research Articles

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance.

Little is known about Nima‐related kinase (NEKs), a widely conserved family of kinases that have key roles in cell‐cycle progression. Nevertheless, it is now clear that multiple NEK family members act in networks, not only to regulate specific events of mitosis, but also to regulate metabolic events independently of the cell cycle. NEK5 was shown to act in centrosome disjunction, caspase‐3 regulation, myogenesis, and mitochondrial respiration. Here, we demonstrate that NEK5 interacts with LonP1, an AAA+ mitochondrial protease implicated in protein quality control and mtDNA remodeling, within the mitochondria and it might be involved in the LonP1‐TFAM signaling module. Moreover, we demonstrate that NEK5 kinase activity is required for maintaining mitochondrial mass and functionality and mtDNA integrity after oxidative damage. Taken together, these results show a new role of NEK5 in the regulation of mitochondrial homeostasis and mtDNA maintenance, possibly due to its interaction with key mitochondrial proteins, such as LonP1.

Cell-Cycle Therapeutics Come of Age.

The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy. Palbociclib, ribociclib, and abemaciclib represent a new class of highly specific ATP-competitive CDK4/6 inhibitors that induce reversible G1-phase cell-cycle arrest in retinoblastoma-positive tumor models. Both palbociclib and ribociclib have been approved in combination with hormone-based therapy for the treatment of naïve hormone receptor-positive advanced breast cancer on the basis of an improvement in progression-free survival. In general, CDK4/6 inhibitors are cytostatic as monotherapy but demonstrate favorable tolerability, which has prompted interest in combination approaches. Combinations with phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitors in breast cancer, and inhibitors of the RAS/RAF/mitogen-activated protein kinase pathway in RAS-mutant cancers are particularly promising approaches that are currently being evaluated. Although the subject of intense preclinical study, predictive biomarkers for response and resistance to these drugs remain largely undefined. CDK4/6 inhibitors have emerged as the most promising of the cell-cycle therapeutics and intense efforts are now underway to expand the reach of this paradigm.

Abstract A28: Analyses of FOXM1 isoforms in ovarian cancer

Abstract Introduction & Objectives: Epithelial ovarian cancer (OC) is the most lethal gynaecological malignancy and the fifth leading cause of cancer death in women in the Western world. Forkhead box M1 (FOXM1) transcription factor was already been described to be overexpressed in various malignancies, playing a key role in cell-cycle progression, chromosomal segregation and genomic stability, and oxidative stress. Moreover, it can also promote drug resistance to herceptin, paclitaxel and cisplatin in breast cancer cells. A recent report from our group has shown, for the first time, that FOXM1 is also overexpressed in OC, being associated with tumor grade. This result seem to indicate an interesting role of this molecule in the progression and resistance to therapy in OC. Our aim is to characterize FOXM1 isoforms in OC through the use of human tissue samples. Material & Methods: Fresh ovarian primary tumors, ascites and peritoneal metastases from patients suffering advanced serous OC were collected from surgery room and processed for microarray analysis to detect FOXM1 expression levels. FOXM1 isoforms were analysed at mRNA expression level by using RTqPCR in a set of new frozen tissue samples. Results: We found that FOXM1 overexpression is increased in OC peritoneal metastases. Now, we are characterizing the isoforms of FOXM1 in primary, ascites and metastatic tumors. Nevertheless, more samples need to be analysed in order to have conclusive results. Conclusions: The present study highlights the role of FOXM1 isoforms in OC dissemination and pursues the idea to elucidate the biologic role of FOXM1 in OC tumorigenesis. Citation Format: Tatiana Altadill, Marina Rigau, Blanca Majem, Lucia Lanau, Josep Castellví, Ángel García, Assumpció Pérez-Benavente, José Luis Sánchez, Silvia Cabrera, Jordi Xercavins, Josep Maria del Campo, Antonio Gil-Moreno, Marta Llauradó, Jaume Reventós. Analyses of FOXM1 isoforms in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A28.

Nucleostemin: a multiplex regulator of cell-cycle progression

Nucleostemin (NS) is a protein concentrated in the nucleolus of most stem cells and also in many tumor cells, which has been implicated in cell-cycle progression owing to its ability to modulate p53. Depletion of NS causes G(1) cell-cycle arrest, but its overexpression does so as well. Recently, this paradox has been clarified. NS overexpression causes a sequestration of murine double minute 2 (MDM2), preventing the destruction of p53. A recent study has demonstrated that loss of NS promotes the interaction of L5 and L11 ribosomal proteins with MDM2 and, thus, also prevents p53 degradation. This new finding expands our understanding of the multiple modes of NS action and reinforces the concept that the nucleolus has key roles in cell-cycle progression.

The Cell Cycle Cdc25A Tyrosine Phosphatase Is Activated in Degenerating Postmitotic Neurons in Alzheimer's Disease

The Cdc25 phosphatases play key roles in cell-cycle progression by activating cyclin-dependent kinases. The latter are absent from neurons that are terminally differentiated in adult brain. However, accumulation of mitotic phosphoepitopes, and re-expression and activation of the M phase regulator, Cdc2/cyclin B, have been described in neurons undergoing degeneration in Alzheimer's disease (AD). To explain this atypical mitotic activation in neurons we investigated the Cdc2-activating Cdc25A phosphatase in human brain. The structural hallmarks of AD neurodegeneration, neurofibrillary tangles and neuritic plaques, were prominently immunolabeled with Cdc25A antibodies. In addition numerous neurons without visible structural alterations were also intensely stained, whereas control brain was very weakly positive. After immunoprecipitation from control and AD tissue, we found that the tyrosine dephosphorylating activity of Cdc25A against exogenous Cdc2 substrate was elevated in AD. Accordingly, Cdc25A from AD tissue displayed increased immunoreactivity with the mitotic phosphoepitope-specific antibody, MPM-2, and co-localized with MPM-2 immunoreactivity in AD neurons. These data suggest that Cdc25A participates in mitotic activation during neurodegeneration. The involvement of Cdc25A in cellular transformation, modulation of the DNA damage checkpoint, and linkage of mitogenic signaling to cell cycle machinery, also implicates one of these cell-cycle pathways in AD pathogenesis.