HIN-1, an inhibitor of cell growth, invasion, and AKT activation.
The HIN-1 gene encoding a small, secreted protein is silenced due to methylation in a substantial fraction of breast, prostate, lung, and pancreatic carcinomas, suggesting a potential tumor suppressor function. The receptor of HIN-1 is unknown, but ligand-binding studies indicate the presence of high-affinity cell surface HIN-1 binding on epithelial cells. Here, we report that HIN-1 is a potent inhibitor of anchorage-dependent and anchorage-independent cell growth, cell migration, and invasion. Expression of HIN-1 in synchronized cells inhibits cell cycle reentry and the phosphorylation of the retinoblastoma protein (Rb), whereas in exponentially growing cells, HIN-1 induces apoptosis without apparent cell cycle arrest and effect on Rb phosphorylation. Investigation of multiple signaling pathways revealed that mitogen-induced phosphorylation and activation of AKT are inhibited in HIN-1-expressing cells. In addition, expression of constitutively activate AKT abrogates HIN-1-mediated growth arrest. Taken together, these studies provide further evidence that HIN-1 possesses tumor suppressor functions, and that these activities may be mediated through the AKT signaling pathway.
Krop
Ian
I
Department of Medical Oncology and Biostatistics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Parker
Michele Taylor
MT
Bloushtain-Qimron
Noga
N
Porter
Dale
D
Gelman
Rebecca
R
Sasaki
Hidefumi
H
Maurer
Matthew
M
Terry
Mary Beth
MB
Parsons
Ramon
R
Polyak
Kornelia
K
D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor; D006801:Humans; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; C434732:SCGB3A1 protein, human; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt