The cyclin-dependent kinase inhibitors p15INK4B and p21CIP1 are critical regulators of fibrillar collagen-induced tumor cell cycle arrest.
The extracellular matrix is a crucial component in determining cell fate. Fibrillar collagen in its native form inhibits cell proliferation, whereas in its monomeric form it stimulates proliferation. The observation of elevated levels of p27(KIP1) in cells plated in the presence of fibrillar collagen has led to the assumption that this kinase inhibitor was responsible for cell cycle arrest on fibrillar collagen. Here we provide evidence that p15(INK4b), rather than p27(KIP1), is the cyclin-dependent kinase inhibitor responsible for G0/G1 arrest of human melanoma cells grown on fibrillar collagen. Additionally, we demonstrate that fibrillar collagen can also arrest cells at the G2 phase, which is mediated in part by p21(CIP1). Our data, in addition to identifying cyclin-dependent kinase inhibitors important in cell cycle arrest mediated by fibrillar collagen, demonstrate the complexity of cell cycle regulation and indicate that modulating a single cyclin-dependent kinase inhibitor does not disrupt cell proliferation in the presence of fibrillar collagen.
Wall
Steven J
SJ
Division of Hematology-Oncology and Department of Pediatrics, University of Southern California and the Saban Research Institute of the Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.
Zhong
Zhi-Duan
ZD
DeClerck
Yves A
YA
D002453:Cell Cycle; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D024022:Fibrillar Collagens / Q000502:physiology*; D016195:G2 Phase; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D016192:Resting Phase, Cell Cycle
D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D024022:Fibrillar Collagens; D050760:Cyclin-Dependent Kinase Inhibitor p27