Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor.
Lymphatic vessels are essential for fluid homeostasis, immune surveillance and fat adsorption, and also serve as a major route for tumor metastasis in many types of cancer. We found that isolated human primary lymphatic and blood vascular endothelial cells (LECs and BECs, respectively) show interesting differences in gene expression relevant for their distinct functions in vivo. Although these phenotypes are stable in vitro and in vivo, overexpression of the homeobox transcription factor Prox-1 in the BECs was capable of inducing LEC-specific gene transcription in the BECs, and, surprisingly, Prox-1 suppressed the expression of approximately 40% of the BEC-specific genes. Prox-1 did not have global effects on the expression of LEC-specific genes in other cell types, except that it up-regulated cyclin E1 and E2 mRNAs and activated the cyclin e promoter in various cell types. These data suggest that Prox-1 acts as a cell proliferation inducer and a fate determination factor for the LECs. Furthermore, the data provide insights into the phenotypic diversity of endothelial cells and into the possibility of transcriptional reprogramming of differentiated endothelial cells.
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute and Helsinki University Central Hospital, Helsinki, Finland.
Tatiana V
TV
Petrova
Taija
T
Mäkinen
Tomi P
TP
Mäkelä
Janna
J
Saarela
Ismo
I
Virtanen
Robert E
RE
Ferrell
David N
DN
Finegold
Dontscho
D
Kerjaschki
Seppo
S
Ylä-Herttuala
Kari
K
Alitalo
D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D020405:Dermis / Q000166:cytology; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein
D015815:Cell Adhesion Molecules; D016213:Cyclins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D018398:Homeodomain Proteins; D018121:Receptors, Cytokine; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein