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Malumbres M.,Cell Division and Cancer Group
Physiological Reviews | Year: 2011

The basic biology of the cell division cycle and its control by protein kinases was originally studied through genetic and biochemical studies in yeast and other model organisms. The major regulatory mechanisms identified in this pioneer work are conserved in mammals. However, recent studies in different cell types or genetic models are now providing a new perspective on the function of these major cell cycle regulators in different tissues. Here, we review the physiological relevance of mammalian cell cycle kinases such as cyclin-dependent kinases (Cdks), Aurora and Polo-like kinases, and mitotic checkpoint regulators (Bub1, BubR1, and Mps1) as well as other less-studied enzymes such as Cdc7, Nek proteins, or Mastl and their implications in development, tissue homeostasis, and human disease. Among these functions, the control of self-renewal or asymmetric cell division in stem/progenitor cells and the ability to regenerate injured tissues is a central issue in current research. In addition, many of these proteins play previously unexpected roles in metabolism, cardiovascular function, or neuron biology. The modulation of their enzymatic activity may therefore have multiple therapeutic benefits in human disease.

Malumbres M.,Cell Division and Cancer Group
Molecular Aspects of Medicine | Year: 2013

microRNAs (miRNAs) are small, non-coding RNAs with critical roles in fine-tuning a wide array of biological processes including development, metabolism, and homeostasis. miRNAs expression, similarly to that of protein-coding genes, is regulated by multiple transcriptional networks as well as the epigenetic machinery. miRNA genes can be epigenetically regulated by DNA methylation or specific histone modifications. In addition, miRNAs can themselves repress key enzymes that drive epigenetic remodeling, generating regulatory circuits that have a significant effect in the transcriptional landscape of the cell. Recent evidences also suggest that miRNAs can directly modulate gene transcription in the nucleus through the recognition of specific target sites in promoter regions. Given the widespread distribution of epigenetic marks and miRNA target sites in the genome, the regulatory circuits linking both mechanisms are likely to have a major impact in genome transcription and cell physiology. Not surprisingly, tumor-associated aberrations in the miRNA or epigenetic machineries are widely distributed in human cancer, and we are just starting to understand their relevance in diagnosis, prognosis or therapy. © 2012 Elsevier Ltd. All rights reserved.

Song M.S.,Harvard University | Carracedo A.,Harvard University | Salmena L.,Harvard University | Song S.J.,Harvard University | And 3 more authors.
Cell | Year: 2011

PTEN is a frequently mutated tumor suppressor gene that opposes the PI3K/AKT pathway through dephosphorylation of phosphoinositide-3,4,5- triphosphate. Recently, nuclear compartmentalization of PTEN was found as a key component of its tumor-suppressive activity; however its nuclear function remains poorly defined. Here we show that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex. We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1. This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss and the tumor-suppressive activity of catalytically inactive PTEN. Importantly, we demonstrate that PTEN mutant and PTEN null states are not synonymous as they are differentially sensitive to pharmacological inhibition of APC-CDH1 targets such as PLK1 and Aurora kinases. This finding identifies a strategy for cancer patient stratification and, thus, optimization of targeted therapies. PaperClip: © 2011 Elsevier Inc.

de Castro I.P.,Cell Division and Cancer Group | Malumbres M.,Cell Division and Cancer Group
Genes and Cancer | Year: 2012

Cell cycle deregulation is a common motif in human cancer, and multiple therapeutic strategies are aimed to prevent tumor cell proliferation. Whereas most current therapies are designed to arrest cell cycle progression either in G1/S or in mitosis, new proposals include targeting the intrinsic chromosomal instability (CIN, an increased rate of gain or losses of chromosomes during cell division) or aneuploidy (a genomic composition that differs from diploid) that many tumor cells display. Why tumors cells are chromosomally unstable or aneuploid and what are the consequences of these alterations are not completely clear at present. Several mitotic regulators are overexpressed as a consequence of oncogenic alterations, and they are likely to alter the proper regulation of chromosome segregation in cancer cells. In this review, we propose the relevance of TPX2, a mitotic regulator involved in the formation of the mitotic spindle, in oncogene-induced mitotic stress. This protein, as well as its partner Aurora-A, is frequently overexpressed in human cancer, and its deregulation may participate not only in chromosome numeric aberrations but also in other forms of genomic instability in cancer cells. © The Author(s) 2013.

De Carcer G.,Cell Division and Cancer Group | Manning G.,La Jolla Salk Institute | Malumbres M.,Cell Division and Cancer Group
Cell Cycle | Year: 2011

Mammalian Polo-like kinases (Plks) are characterized by the presence of an N-terminal protein kinase domain and a C-terminal Polo Box Domain (PBD) involved in substrate binding and regulation of kinase activity. Plk1-4 have traditionally been linked to cell cycle progression, genotoxic stress and, more recently, neuron biology. Recently, a fifth mammalian Plk family member, Plk5, has been characterized in murine and human cells. Plk5 is expressed mainly in differentiated tissues such as the cerebellum. Despite apparent loss of catalytic activity and a stop codon in the middle of the human gene, Plk5 proteins retain important functions in neuron biology. Notably, its expression is silenced by epigenetic alterations in brain tumors such as glioblastomas, and its re-expression prevents cell proliferation of these tumor cells. In this review, we will focus on the non-cell cycle roles of Plks, the biology of the new member of the family, and the possible kinase- and PBD-independent functions of Polo-like kinases. © 2011 Landes Bioscience.

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