Sam68 haploinsufficiency delays onset of mammary tumorigenesis and metastasis.
The Src-associated substrate in mitosis Sam68 is a KH type RNA-binding protein known to be a substrate of numerous tyrosine kinases, and often referred to as a STAR (signal transduction activator of RNA) protein. Herein, we observed that Sam68-null mice display mammary gland and the uterine development defects. Moreover, we report that Sam68 haploinsufficiency impedes mammary tumor onset in vivo driven by the potent mammary-targeted polyoma middle T-antigen (MMTV-PyMT) oncogene. The effect was cell autonomous as the Sam68 knockdown in PyMT-transformed cell lines also delayed tumorigenesis and metastasis formation in nude mice. Interestingly, tumor extracts isolated from PyMT/Sam68(+/-) mice compared with PyMT/Sam68(+/+) mice contained activated Src and FAK kinases. These findings suggest that Sam68 may be a modulator of tyrosine kinase activity in vivo and a signaling requirement for mammary tumorigenesis and metastasis.
Richard
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S
Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Sir Mortimer B Davis Jewish General Hospital, Lady Davis Institute for Medical Research, Montréal, Québec, Canada. stephane.richard@mcgill.ca
Vogel
G
G
Huot
M-E
ME
Guo
T
T
Muller
W J
WJ
Lukong
K E
KE
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics; D000081247:CSK Tyrosine-Protein Kinase; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D006579:Heterozygote; D008175:Lung Neoplasms / Q000556:secondary; D008321:Mammary Glands, Animal / Q000002:abnormalities / Q000254:growth & development; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D011120:Polyomavirus / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D047368:Tumor Burden / Q000235:genetics; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000002:abnormalities / Q000254:growth & development; D019061:src-Family Kinases
D048868:Adaptor Proteins, Signal Transducing; D000957:Antigens, Viral, Tumor; C513253:Khdrbs1 protein, mouse; D016601:RNA-Binding Proteins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases