Marcos Malumbres

Publications (129) View all

• Source

  Available from: Marcos Malumbres

  Article: Killing cells by targeting mitosis.

  E Manchado, M Guillamot, M Malumbres
  [show abstract] [hide abstract]
  ABSTRACT: Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis. As the efficacy of cell-cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic.
  Cell death and differentiation 03/2012; 19(3):369-77. · 8.24 Impact Factor
• Source

  Available from: Marcos Malumbres

  Article: Genetic cooperation between p21Cip1 and INK4 inhibitors in cellular senescence and tumor suppression.

  V Quereda, J Martinalbo, P Dubus, A Carnero, M Malumbres
  [show abstract] [hide abstract]
  ABSTRACT: Cell-cycle inhibitors of the Cip/Kip and INK4 families are involved in cellular senescence and tumor suppression. Some of these proteins, p21(Cip1), p16(INK4a) and p15(INK4b), are coexpressed in response to antiproliferative signals such as cellular senescence resulting in cell-cycle arrest. To understand the roles of these inhibitors and their synergistic effect, we have characterized the growth properties and senescent behavior of primary cells deficient in p21(Cip1) and expressing an endogenous Cdk4(R24C) (cyclin-dependent kinase) mutant (Cdk4(R24C) knock-in cells) insensitive to INK4 proteins. Inactivation of both p21(Cip1) and INK4 pathways strongly cooperate in suppressing cellular senescence in vitro. These double mutant cells behavior as immortal cultures and display high sensitivity to cellular transformation by oncogenes. Moreover, mice double mutant in the INK4 and p21(Cip1) pathways (Cdk4(R24C); p21(Cip1)-null mice) display an increased incidence of specific sarcomas, suggesting a significant cooperation between these two families of cell-cycle inhibitors in senescence responses and tumor suppression in vivo.
  Oncogene 01/2008; 26(55):7665-74. · 6.37 Impact Factor
• Source

  Available from: Marcos Malumbres

  Chapter: Preclinical Models for Cell Cycle-Targeted Therapies

  M. Malumbres
  09/2006: pages 139-147;
• Source

  Available from: Marcos Malumbres

  Article: Cyclin-dependent kinase 2 is dispensable for normal centrosome duplication but required for oncogene-induced centrosome overduplication.

  A Duensing, Y Liu, M Tseng, M Malumbres, M Barbacid, S Duensing
  [show abstract] [hide abstract]
  ABSTRACT: Cyclin-dependent kinase 2 (CDK2) has been proposed to function as a master regulator of centrosome duplication. Using mouse embryonic fibroblasts (MEFs) in which Cdk2 has been genetically deleted, we show here that CDK2 is not required for normal centrosome duplication, maturation and bipolar mitotic spindle formation. In contrast, Cdk2 deficiency completely abrogates aberrant centrosome duplication induced by a viral oncogene. Mechanistically, centrosome overduplication in MEFs wild-type for Cdk2 involves the formation of supernumerary immature centrosomes. These results indicate that normal and abnormal centrosome duplication have significantly different requirements for CDK2 activity and point to a role of CDK2 in licensing centrosomes for aberrant duplication. Furthermore, our findings suggest that CDK2 may be a suitable therapeutic target to inhibit centrosome-mediated chromosomal instability in tumor cells.
  Oncogene 06/2006; 25(20):2943-9. · 6.37 Impact Factor
• Source

  Available from: Marcos Malumbres

  Article: Cell cycle and cancer: genetic analysis of the role of cyclin-dependent kinases.

  M Barbacid, S Ortega, R Sotillo, J Odajima, A Martín, D Santamaría, P Dubus, M Malumbres
  [show abstract] [hide abstract]
  ABSTRACT: Most human tumors harbor mutations that misregulate the early phases of the cell cycle. Here, we summarize genetic evidence, mostly obtained in our laboratory using strains of gene-targeted mice, that provides direct experimental support for a role of Cdk4 in tumor development. Moreover, these genetic studies challenge some well-established concepts regarding the role of Cdks during the early phases of the cell cycle. For instance, they have illustrated that Cdk4 and Cdk6 are not essential for cell division during embryonic development except in the hematopoietic system. More surprisingly, mice lacking Cdk2 survive for over 2 years without detectable abnormalities except in their germ cells, indicating that Cdk2 is essential for meiosis but dispensable for the normal mitotic cell cycle. Cdk2 is also dispensable for cell cycle inhibition and tumor suppression by the Cip/Kip inhibitors, p21(Cip1) and p27(Kip1). These observations have important implications not only to understand cell cycle regulation, but also to validate Cdks as potential targets for the development of therapeutic strategies to block proliferation of tumor cells.
  Cold Spring Harbor Symposia on Quantitative Biology 02/2005; 70:233-40.