Frame, Margaret

Wilkinson, Simon

Aldridge, Roland Christopher Lochore

Wellcome Trust

2018-08-29T10:37:41Z

2018-08-29T10:37:41Z

2018-11-30

Cyclin-Dependent Kinase 11 (CDK11) is a serine/threonine kinase encoded at human locus 1p36.3 by two paralogous genes CDK11A and CDK11B. CDK11 has diverse roles in the regulation of transcription, splicing, apoptosis and mitosis. In proliferating cells, two predominant isoforms are expressed: CDK11p58 and CDK11p110. CDK11p110 is expressed throughout the cell cycle and regulates transcription and splicing. CDK11p58 is expressed at mitosis via IRES-dependent translation; it mediates mitotic progression and faithful chromosome segregation. Loss of Cdk11 in murine models causes early embryonic lethality, demonstrating that CDK11 is essential for normal development. Furthermore, dysregulated CDK11 expression is associated with numerous late-onset disease states, indicating its importance in adult life. In cancer, abnormal expression of CDK11 correlates with poor prognosis in a variety of tumours. Moreover, deletion of the chromosomal region 1p36.3, containing the CDK11 locus, is frequently observed in cancer and has recently been identified in a case of the development disorder, Cornelia de Lange Syndrome (CdLS). This thesis aimed to examine the functions of CDK11 and the impact of their dysregulation in cancer and developmental phenotypes. The initial aim was to investigate the novel role for CDK11 in regulating autophagy in cancer cells; CDK11 depletion causes a marked autophagy phenotype, with accumulation of autophagy protein LC3. I demonstrate that this CDK11-mediated autophagy occurs as a consequence of mitotic dysregulation. Subsequently, I examined the role of autophagy following aberrant mitosis and chromosome missegregation. I show that autophagy is important in the maintenance of aneuploid karyotypes, with loss of autophagy impairing the survival of aneuploid cell populations. I then investigated the effects of CDK11 in regulating cancer cell motility and determined that CDK11 depletion retards cancer cell migration. However, I was unable to identify any failure in cell adhesion or cell polarization to explain this migration phenotype. Subsequently, I interrogated the CDK11 interactome to further characterize the mechanisms through which CDK11 regulates both novel and established functions. This work indicated the involvement of the distinct CDK11 isoforms in pathways that have not previously been reported. This included the interaction of CDK11p110 with ribosomal and spliceosomal proteins during mitosis and the interaction of CDK11p58 with spliceosomal and proteosomal constituents also during mitosis. These findings may provide the foundation for further study. Finally I describe work undertaken to sequence the CDK11 locus in a cohort of CdLS patients, with no known causative genetic mutation, to investigate CDK11A/CDK11B as candidate disease-associated genes. Although no causative mutation in CDK11A or CDK11B was identifying, sequencing of this region indicated NCBI and UCSC genome assemblies of this locus were inaccurate due to the genomic duplication. This has been confirmed by others and corrected in the most recent genome assemblies.

http://hdl.handle.net/1842/31527

en

The University of Edinburgh

Cyclin-Dependent Kinase 11

CDK11

autophagy

Investigating the influence of CDK11 in developmental and cancer phenotypes

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy