Proliferation-specific genes activated by Galpha(12): a role for PDGFRalpha and JAK3 in Galpha(12)-mediated cell proliferation.
Galpha(12), the alpha-subunit of G protein G12, is ubiquitously expressed and it has been identified as a putative "causative oncogene" of soft-tissue sarcomas. Overexpression of wild-type or GTPase-deficient mutant of Galpha(12) (Galpha(12)Q229L or Galpha(12)QL) leads to the oncogenic transformation of NIH3T3 cells. Galpha(12)QL-tramsformed NIH3T3 cells show a distinct oncogenic phenotype defined by increased cell proliferation, anchorage-independent growth, reduced growth-factor dependency, attenuation of apoptotic signals, and neoplastic cytoskeletal changes. In this study, the genes contributing to the reduced growth-factor dependency of Galpha(12)QL-NIH3T3 cells were identified by transcription profiling of serum-starved Galpha(12)QL-transformed NIH3T3 (Galpha(12)QL-NIH3T3) cells. Results from these studies indicate that Galpha(12)QL stimulates the expression of genes that promote cell growth. The increased expressions of growth-promoting genes in Galpha(12)QL-NIH3T3 cells were validated by semiquantitative reverse transcription-polymerase chain reaction and immunoblot analyses. Further studies aimed at investigating the critical role of two of such upregulated genes, namely PDGFRalpha and JAK3, indicated that the inhibition of PDGFRalpha or JAK3 activity-attenuated Galpha(12)QL-mediated serum-independent cell proliferation. These studies point to possible novel autocrine and/or paracrine control mechanisms involving PDGFRalpha and JAK3 in Galpha(12)-mediated proliferation and oncogenesis.
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA.
Rashmi N
RN
Kumar
V
V
Radhika
Valéry
V
Audigé
Santosh G
SG
Rane
N
N
Dhanasekaran
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000737:chemistry / Q000502:physiology*; D053616:Janus Kinase 3 / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
D008024:Ligands; D020796:Receptor, Platelet-Derived Growth Factor alpha; D053616:Janus Kinase 3; D020558:GTP Phosphohydrolases; D044365:GTP-Binding Protein alpha Subunits, G12-G13