Apoptotic Signalling

Maréne Landström

Section leader

Maréne Landström
Marene.Landstrom(AT)LICR.uu.se
Phone +46 18 160406

TGF-ß plays an important role for regulating of cell fate (i.e. proliferation, migration, differentiation and apoptosis) during embryogenesis. TGF-ß inhibits proliferation and induces apoptosis in most normal cell types while during tumor progression, TGF-ß instead promotes tumor growth due to its effects on transdifferentiation of cells, angiogenesis and immunosurveillance.

Smad7 is a target gene for TGF-ß, and we have demonstrated that Smad7 is required for TGF-ß-induced apoptosis in prostate cancer cells, as well as in human keratinocytes (Landström et al., 2000). Furthermore, we have recently reported that Smad7 facilitates the TGF-ß-activating kinase 1 (TAK1), mitogen activated protein kinase kinase 3 (MKK3) and p38 mitogen activated protein (MAP) kinase pathway, presumably by acting as an adaptor protein bringing the kinases close to each other (Edlund et al., 2003, Fig. 1). As Smad7 is facilitating the activation of p38, we are currently investigating possible novel target proteins downstream of the active p38-Smad7 complex, in the apoptotic signalling pathway.
Moreover, we have discovered a novel function for Smad7 as a regulator of the actin cytoskeleton, as Smad7 was found to be required for the activation of the small GTPase Cdc42 (Edlund et al., 2004).

The aim of our work is to further investigate the role of Smad7 for TGF-ß -induced regulation of cellular fate with particular emphasis on the apoptotic signalling pathway.

  • We have earlier described
    a previously unknown function for Smad7 as an adaptor protein in the TAK1-MKK3-p38 MAPK pathway. We are currently, in more detail, investigating how TGF-ß and Smad7 can activate this pathway.
  • We are investigating potential substrates for the
    Smad7 – p38 MAPK complex, which can act as regulators for TGF-ß- induced apoptosis in prostate cancer cells.
  • Smad7 is a nuclear protein which upon TGF-ß stimulation of cells is exported to the cytoplasm (Itoh et al., 1998). We are interested in the potential effects of Smad7 on gene regulation and have therefore performed microarray analyses on cells over-expressing Smad7. The possible candidate genes are currently validated.

Fig. 2. Expression of Smad proteins in prostate cancer cells.

 
  • We have observed increased expression of the receptor-activated Smads (Smad2, Smad3 and Smad4) as well as the inhibitory Smad6 and Smad7 in normal and malignant prostate epithelial cells in vivo, preceding apoptosis induced by androgen withdrawal (Brodin et al., 1999, Fig. 2). The presence of Smad7 in apoptotic cells in vivo, together with our previous observation that Smad7 is required for induction of apoptosis, encourage us to continue our search for the detailed molecular mechanisms for how Smad7 can act as a mediator for TGF-ß induced apoptosis in epithelial cells.
 

2008 Oct;10(10):1199-207. Epub 2008 Aug 31
Selected Publications
Publications 2009-2010 (see also annual reports)

Hamidi A, von Bulow V, Hamidi R, Winssinger N, Barluenga S, Heldin C-H, Landström M. Polyubiquitination of TAK1 mediates nuclear factor-kappa B activation in response to different inflammatory stimuli. Journal Biological Chemistry, in press.

Mu Y, Sundar R, Thakur N, Ekman M, Kumar S, Yakymovych M, Dimitrou L, Hermansson A, Bengoechea-Alonso MT, Ericsson J, Heldin C-H, Landström M. TRAF6 ubiquitinates TGFß type I receptor to promote its cleavage and nuclear translocation in cancer. Nature Communications2, 2011, 330 DOI: i.10.1038/ncomms1332

Trani M, Sorrentino A, Busch C, Landström M. Pro-apoptotic effect of aurothiomalate in prostate cancer cells. Cell Cycle 2009 Jan 15;8(2):306-13. Epub 2009 Jan 10.

Sorrentino A, Thakur N, Grimsby S, Marcusson A, Bulow v V, Zhang S, Schuster N, Heldin CH, Landström M. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner.Nature Cell Biology

Davoodpour P, Landström M, Welsh M. Increased apoptosis and c-Abl activity in PC3 prostate cancer cells overexpressing the Shb adapter protein. BMC Cancer. 2007, 7:161.

Zhang S, Ekman M, Thakur N, Bu S, Davoodpour P, Grimsby S, Tagami S, Heldin C-H, Landström M. TGF-ß1-induced activation of ATM and p53 is mediated by Smad7. Cell Cycle. 2006, (23):2787-95.

Davoodpour P, Landström M. 2-Methoxyestradiol-induced apoptosis in prostate cancer cells requires Smad7. Journal Biological Chemistry 280: 14773-14779, 2005 (E-publ. Feb 11; 2005).

Edlund S, Lee SY, Grimsby S, Zhang S, Aspenström P, Heldin C-H, Landström M. Interaction between Smad7 and ß-catenin: Importance for TGF-ß-induced apoptosis. Molecular Cell Biology4, 1475-88, 2005.

Davoodpour P, Bergström M, Landström M. Effects of 2-methoxyestradiol on human prostate cancer cell aggregates on apoptosis, proliferation, and PET-tracer uptake. Nucelar Medicine and Biology, Vol 31/7 pp. 867-874, 2004.

Edlund S, Landström M, Heldin C-H, Aspenström P. Smad7 is required for TGF-ß induced activation of the small GTPase Cdc42. Journal of Cell Science, 117, 1835-1847, 2004.

Edlund S, Bu S, Schuster N, Aspenström P, Heldin N-E, ten Dijke P, Heldin C-H, Landström M. TGF-ß1-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TAK1 and MKK3. Molecular Biology of the Cell 14:529-544, 2003.

Bu S, Blaukat A, Fu X, Heldin N-E, Landström M. 2-Methoxyestradiol-induced apoptosis of Bcl-2 expressing breast and prostate carcinoma cells. FEBS Letters 531:141-151, 2002.

Edlund S, Landström M, Heldin C-H, Aspenström P. TGF-ß-induced mobilisation of the actin cytoskeleton requires signalling by the small GTPases Cdc42 and RhoA. Molecular Biology of the Cell 13, 902-14, 2002.

Landström M, Heldin N-E, Bu S, Hermansson A, Itoh S, ten Dijke P, Heldin C-H. Smad7 mediates TGF-ß1 induced apoptosis in prostatic carcinoma cells. Current Biology 10:535-538,

Korchynskyi O, Landström M, Stoika R, Funa K, Heldin C-H, ten Dijke P, Souchelnytskyi, S. Expression of Smad proteins in human colorectal cancer. International Journal of Cancer 82:197-202, 1999.

Brodin G, ten Dijke P, Funa K, Heldin C-H, Landström M. Increased Smad Expression and Activation is Associated with Apoptosis in Normal and Malignant Prostate after Castration. Cancer Research 59:2731-2738, 1999.

Itoh S*, Landström M*, Itoh F, Heldin N-E, Hermansson A, Heldin C-H, ten Dijke P. Transforming growth factor TGF-ß1 induced nuclear export of Smad7. Journal Biological Chemistry.273:29195-29201, 1998. *joints first authors
REVIEWS

Sundar R. and Landström M. TRAF6. Encyclopedia of Signaling Molecules. Springer Major Reference Work. Invited review, accepted pending revision.

Mu Y, Kumar SK, Landström M. Non-Smad signaling pathways.Cell and Tissue Research. Invited review. In press June 2011.

Landström M. The TAK1-TRAF6 signaling pathway. International Journal of Biochemistry and Cell Biology. 2010 42 (5): 585-589.

Thakur N, Sorrentino A, Heldin C-H, Landström M.TGF-ß uses the E3-ligase TRAF6 to turn on the kinase TAK1 to kill prostate cancer cells. Future Oncology Feb 5(1):1-3.Invited Editorial.

Heldin C-H, Landstrom M, Moustakas A.Mechanism of TGF-ß signaling to growth arrest, apoptosis and epithelial-mesenchymal transition.Current Opinion in Cell Biology,21:1-11, 2009.

Landström M.Nyupptäckt signalväg kan ge säkrare prognos för prostatacancer.Onkologi i SverigeNr 6, 2008.

 

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