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RASSF1A Elicits Apoptosis through an MST2 Pathway Directing Proapoptotic Transcription by the p73 Tumor Suppressor Protein
Open accessAbstract
SUMMARY RASSF1A is a tumor suppressor gene that is epigenetically silenced in a wide variety of sporadic human malignancies. Expression of alternative RASSF1 isoforms cannot substitute for RASSF1A-promoted cell-cycle arrest and apoptosis. Apoptosis can be driven by either activating Bax or by activation of MST kinases. The Raf1 proto-oncogene binds to MST2, preventing its activation and proapoptotic signaling. Here we show that key steps in RASSF1A-induced apoptosis are the disruption of the inhibitory Raf1-MST2 complex by RASSF1A and the concomitant enhancement of MST2 interaction with its substrate, LATS1. Subsequently, RASSF1A-activated LATS1 phosphorylates and releases the transcriptional regulator YAP1, allowing YAP1 to translocate to the nucleus and associate with p73, resulting in transcription of the proapoptotic target gene puma. Our results describe an MST2-dependent effector pathway for RASSF1A proapoptotic signaling and indicate that silencing of RASSF1A in tumors removes a proapoptotic signal emanating from p73.
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Brennecke, J., Hipfner, D. R., Stark, A., Russell, R. B., & Cohen, S. M. (2003) · Cell · doi:10.1016/s0092-8674(03)00231-9 · Cited by 2,042
Mass spectrometry–based proteomics turns quantitative
Ong, S.-E., & Mann, M. (2005) · Nature Chemical Biology · doi:10.1038/nchembio736 · Cited by 1,572 · cited 1×
“Quantitative proteomics methods that can capture dynamic changes in protein expression or interactions (Gingras et al., 2007; Ong and Mann, 2005) Matallanas et al.”
Basu, S., Totty, N. F., Irwin, M. S., Sudol, M., & Downward, J. (2003) · Molecular Cell · doi:10.1016/s1097-2765(02)00776-1 · Cited by 843
The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1
Chan, E. H. Y., Nousiainen, M., Chalamalasetty, R. B., Schäfer, A., Nigg, E. A., & Silljé, H. H. W. (2005) · Oncogene · doi:10.1038/sj.onc.1208445 · Cited by 584
Cited by
Calvo, F., Ege, N., Grande-Garcia, A., Hooper, S., Jenkins, R. P., Chaudhry, S. I., Harrington, K., Williamson, P., Moeendarbary, E., Charras, G., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2756 · Cited by 1,478
The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal
Zhao, B., Tumaneng, K., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2303 · Cited by 1,205
Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies
Bahar, M. E., Kim, H. J., & Kim, D. R. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01705-z · Cited by 888
PUMA, a potent killer with or without p53
Yu, J., & Zhang, L. (2008) · Oncogene · doi:10.1038/onc.2009.45 · Cited by 554
Raf Family Kinases: Old Dogs Have Learned New Tricks
Matallanas, D., Birtwistle, M., Romano, D., Zebisch, A., Rauch, J., von Kriegsheim, A., & Kolch, W. (2011) · Genes & Cancer · doi:10.1177/1947601911407323 · Cited by 386
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Metadata
- Authors
- Matallanas, D., Romano, D., Yee, K., Meissl, K., Kucerova, L., Piazzolla, D., Baccarini, M., Vass, J. K., Kolch, W., & O'Neill, E.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 27
- Issue
- 6
- Pages
- 962-975
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2027928327
- Cited by
- 416
- References
- 4
- FWCI
- 9.30
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Matallanas, D., Romano, D., Yee, K., Meissl, K., Kucerova, L., Piazzolla, D., Baccarini, M., Vass, J. K., Kolch, W., & O'Neill, E. (2007). RASSF1A Elicits Apoptosis through an MST2 Pathway Directing Proapoptotic Transcription by the p73 Tumor Suppressor Protein. Molecular Cell. https://doi.org/10.1016/j.molcel.2007.08.008
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