The tumor suppressor functions of p27(kip1) include control of the mesenchymal/amoeboid transition.
In many human cancers, p27 downregulation correlates with a worse prognosis, suggesting that p27 levels could represent an important determinant in cell transformation and cancer development. Using a mouse model system based on v-src-induced transformation, we show here that p27 absence is always linked to a more aggressive phenotype. When cultured in three-dimensional contexts, v-src-transformed p27-null fibroblasts undergo a morphological switch from an elongated to a rounded cell shape, accompanied by amoeboid-like morphology and motility. Importantly, the acquisition of the amoeboid motility is associated with a greater ability to move and colonize distant sites in vivo. The reintroduction of different p27 mutants in v-src-transformed p27-null cells demonstrates that the control of cell proliferation and motility represents two distinct functions of p27, both necessary for it to fully act as a tumor suppressor. Thus, we highlight here a new p27 function in driving cell plasticity that is associated with its C-terminal portion and does not depend on the control of cyclin-dependent kinase activity.
Berton
Stefania
S
Division of Experimental Oncology 2, Centro di Riferimento Oncologico, Aviano, Italy.
Belletti
Barbara
B
Wolf
Katarina
K
Canzonieri
Vincenzo
V
Lovat
Francesca
F
Vecchione
Andrea
A
Colombatti
Alfonso
A
Friedl
Peter
P
Baldassarre
Gustavo
G
D000818:Animals; D002461:Cell Line, Transformed; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D010641:Phenotype; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D050505:Mutant Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015688:Oncogene Protein pp60(v-src); D020742:rhoA GTP-Binding Protein