Cyclin D1 regulates cellular migration through the inhibition of thrombospondin 1 and ROCK signaling

Zhiping Li1, Chenguang Wang, Xuanmao Jiao

  • 1Thomas Jefferson University, Department of Cancer Biology, Kimmel Cancer Center, Bluemle Building, Rm 1050, 233 South 10th St, Philadelphia, PA 19107, USA.

Insights

Cyclin D1, overexpressed in tumors, promotes cell motility by inhibiting Rho-activated kinase II (ROCKII) signaling and repressing metastasis suppressor thrombospondin 1 (TSP-1). Loss of cyclin D1 increases adhesion and decreases motility.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Cyclin D1 is frequently overexpressed in human tumors and linked to metastasis.
  • Activation of Rho GTPases induces cyclin D1 expression.
  • The precise role of cyclin D1 in regulating cell adhesion and motility remains incompletely understood.

Purpose of the Study:

  • To investigate the role of cyclin D1 in regulating cellular adhesion, motility, and associated molecular pathways.
  • To identify genes regulated by cyclin D1 that influence cell migration.
  • To elucidate the mechanism by which cyclin D1 affects cell metastasis.

Main Methods:

  • Utilized cyclin D1-deficient mouse embryo fibroblasts (MEFs) and wild-type MEFs for comparative analysis.
  • Employed retroviral transduction to reintroduce cyclin D1 into deficient cells.
  • Performed mutational analysis of cyclin D1, genomewide expression arrays, and Rho GTPase activity assays.

Main Results:

  • Cyclin D1 deficiency led to increased cell adhesion and decreased motility, which were reversed by cyclin D1 reintroduction.
  • Cyclin D1 regulates genes including Rho-activated kinase II (ROCKII) and thrombospondin 1 (TSP-1).
  • Cyclin D1-deficient cells exhibited elevated Rho GTP, ROCKII activity, and downstream signaling, alongside repressed ROCKII and TSP-1 expression.

Conclusions:

  • Cyclin D1 promotes cellular motility by inhibiting ROCK signaling pathways.
  • Cyclin D1 acts as a repressor of the metastasis suppressor TSP-1.
  • Targeting cyclin D1 or its downstream effectors may offer therapeutic strategies for inhibiting cancer metastasis.

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