Transforming growth factor-beta responsiveness in DPC4/SMAD4-null cancer cells.
DPC4/SMAD4 is a candidate tumor suppressor gene with a strikingly high frequency of gene alterations in pancreatic cancer that suggests a discrete role for DPC4 in these tumors. DPC4 tumor-suppressive function has been implicated to mediate the transforming growth factor-beta (TGFbeta)-suppressive pathway; however, in a DPC4-null pancreatic cancer cell line, TGFbeta growth-inhibitory and transcriptional responses were found to be DPC4-independent. This was observed within native cells having a natural homozygous deletion and in clones engineered for stable expression of wild-type DPC4 integrated into the genome. This observation contrasted with the absolute DPC4 dependence of TGFbeta responses in a breast cancer cell line studied in parallel. This growth-inhibitory response to TGFbeta in DPC4-null cells relied on an intact ras effector pathway. These data further suggest a major categorization of TGFbeta responses into DPC4-dependent and -independent signaling pathways and specifically suggest that disruption of the TGFbeta-independent signal might be a basis of selection for the emergence of DPC4 alterations during tumorigenesis in the pancreas and other sites.
Dai
J L
JL
Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Schutte
M
M
Bansal
R K
RK
Wilentz
R E
RE
Sugar
A Y
AY
Kern
S E
SE
D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D051901:Smad4 Protein; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000502:physiology
D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018631:ras Proteins