Increased Rac activity is required for the progression of T-lymphomas induced by Pten-deficiency.
Mutation of the tumor suppressor PTEN results in loss of its PI3-kinase counteracting function. PI3-kinase stimulates tumor formation by PKB/Akt-mediated cell proliferation and prevention of apoptosis. PI3-kinase may also activate Rho-GTPases and their regulatory GEFs to promote invasion. Here we have analyzed the function of the Rac-specific activator, Tiam1, in PI3-kinase-induced T-lymphomagenesis. Mice with a T cell-specific Pten deletion developed T-lymphomas with enhanced PKB/Akt phosphorylation. However, these T-lymphomas infiltrated more frequently into various organs in Tiam1-deficient mice compared to wild type mice. Surprisingly, Tiam1-deficient lymphomas showed increased Rac activity, suggesting that the lack of Tiam1 is compensated by alternative Rac-activating mechanisms that lead to increased progression of PI3-kinase-induced T-lymphomas.
Strumane
Kristin
K
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Song
Ji-Ying
JY
Baas
Inge
I
Collard
John G
JG
D000818:Animals; D018450:Disease Progression; D017353:Gene Deletion; D020662:Guanine Nucleotide Exchange Factors / Q000494:pharmacology*; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1
D020662:Guanine Nucleotide Exchange Factors; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human