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Cell cycle control by components of cell anchorage

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posted on 2024-09-03, 01:49 authored by Annica Gad

Extracellular factors, such as growth factors and cell anchorage to the extracellular matrix, control when and where cells may proliferate. This control is abolished when a normal cell transforms into a tumour cell. The control of cell proliferation by cell anchorage was elusive and less well studied than the control by growth factors. Therefore, we aimed to clarify at what points in the cell cycle and through which molecular mechanisms cell anchorage controls cell cycle progression. In addition, we wanted to clarify if two components involved in cell anchorage, the hyaluronic acid (HA) -binding domain of CD44 and p21-activated kinase 1 (PAK1), can control cell cycle progression.

Growth factors and cell anchorage have been considered to regulate cell proliferation exclusively by a joint control in the early/mid-G1-phase of the cell cycle. However, we found that in addition to this joint control, cell anchorage also controls progression through the late G1-phase as well as through the final cell division, cytokinesis. The control by cell anchorage in late G1-phase was found to be distinct from the control by growth factors in that it occurs after and independent of the normal control by serum, cyclin D-associated kinase activity, pRb and p107. In addition, we observed that although cells lacking anchorage could initiate the ingression of the cleavage furrow during cytokinesis, they could not complete cell division without cell anchorage. This anchoragedependent control of cytokinesis could be mediated by various integrins as well as by integrinindependent cell anchorage.

Furthermore, we showed that the kinase-inhibitory domain of PAK1 could inhibit the induction of cyclin D1 and cyclin D2 as well as G1-phase progression. Surprisingly, the cell cycle inhibition of the PAK1 kinase-inhibitory domain appeared not to act through inhibiting PAK1 kinase activity, but through a different mechanism.

We also found that the recombinant hyaluronic acid-binding domain of the cell surface receptor CD44 (CD44-HABD) could inhibit endothelial cell cycle progression, angiogenesis and tumour growth. A mutant CD44-HABD without the ability to disturb the binding of CD44 to hyaluronic acid also inhibited cell cycle progression. Therefore, we rule out the possibility that the observed cell cycle inhibition was due to loss of CD44 binding to hyaluronic acid. We hypothesize that the recombinant domain of CD44 inhibits cell cycle progression by binding to an unidentified cell surface ligand.

A normal tissue cell can transform into a tumour cell only if it manages to overcome the control exerted by the surrounding extracellular matrix. Our results reveal that cell anchorage controls the cell cycle at additional steps as compared to growth factors. This finding underscores the importance of the cell anchorage-dependent control in the protection against cellular transformation and tumourigenesis. The anchorage of a cell to the surrounding extracellular matrix also needs to be altered at later stages of tumour progression. Thereby, further elucidation of how cell anchorage controls cell proliferation may provide means allowing the development of new therapies for cancer. This is further emphasised by our findings that domains of proteins involved in cell anchorage, such as CD44 and PAK1, can exert control of the cell cycle, and inhibit tumour cell growth.

List of scientific papers

I. Gad A, Thullberg M, Dannenberg JH, te Riele H, Stromblad S (2004). Retinoblastoma susceptibility gene product (pRb) and p107 functionally separate the requirements for serum and anchorage in the cell cycle G1-phase. J Biol Chem. 279(14): 13640-4. Epub 2004 Jan 19
https://pubmed.ncbi.nlm.nih.gov/14732703

II. Gad A, Thullberg M, Stromblad S (2005). Cell anchorage controls the final contraction of the acto-myosin ring during cytokinesis. [Manuscript]

III. Thullberg M, Gad A, Chernoff J, Stromblad S (2005). The kinase-inhibitory domain of p21-activated kinase 1 inhibits cell cycle progression independent of PAK1 kinase activity. [Manuscript]

IV. Pall T, Gad A, Kasak L, Drews M, Stromblad S, Kogerman P (2004). Recombinant CD44-HABD is a novel and potent direct angiogenesis inhibitor enforcing endothelial cell-specific growth inhibition independently of hyaluronic acid binding. Oncogene. 23(47): 7874-81.
https://pubmed.ncbi.nlm.nih.gov/15361838

History

Defence date

2005-08-26

Department

  • Department of Laboratory Medicine

Publication year

2005

Thesis type

  • Doctoral thesis

ISBN-10

91-7140-359-0

Number of supporting papers

4

Language

  • eng

Original publication date

2005-08-05

Author name in thesis

Gad, Annica

Original department name

Department of Laboratory Medicine

Place of publication

Stockholm

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