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Group members
 HAMLET - a folding variant of alpha-lactalbumin from human milk that induces apoptosis in tumor cells and kills bacteria.
Technician
J. Pettersson
Student
O. Hallgren
Student
L. Gustafsson
PhD
T. Manolov
Student
P. Brest
Post Doc

 

We recently identified a protein complex in the human milk that selectively induces apoptosis in tumor cells and immature cells. The protein component is a folding variant of a-lactalbumin in a partially unfolded state stabilised by a fatty acid. This complex binds to the cell surface, activates mitochondria and reaches the cell nuclei where it accumulates. Nuclear uptake occurs exclusively in cells that are sensitive to the apoptosis - inducing activity of the protein. Recent studies have also shown that the complex kills streptococci but not other bacteria.

Continued studies aim to:

  1. Elucidate the structural basis for apoptosis- inducing activity in the protein complex.
  2. Identify cellular targets of the protein, and the difference between tumor cells and healthy cells.
  3. Study protection in animal models.
  4. Identify similarities in cell killing mechanisms between tumor cells and streptococci.

Further information will soon follow.

 

Recent publications

Peer reviewed papers

P1. Hakansson, A., B. Zhivotovsky, S. Orrenius, H. Sabharwal, and C. Svanborg. 1995. Apoptosis induced by a human milk protein. Proc Natl Acad Sci U S A 92:8064.

P2. Hakansson, A., J. Andreasson, B. Zhivotovsky, D. Karpman, S. Orrenius, and C. Svanborg. 1999. Multimeric alpha-lactalbumin from human milk induces apoptosis through a direct effect on cell nuclei. Exp Cell Res 246:451.

P3. Svensson, M., H. Sabharwal, A. Hakansson, A. K. Mossberg, P. Lipniunas, H. Leffler, C. Svanborg, and S. Linse. 1999. Molecular characterization of alpha-lactalbumin folding variants that induce apoptosis in tumor cells. J Biol Chem 274:6388.

P4. Kohler, C., A. Hakansson, C. Svanborg, S. Orrenius, and B. Zhivotovsky. 1999. Protease activation in apoptosis induced by MAL. Exp Cell Res 249:260.

P5. Hakansson, A., M. Svensson, A. K. Mossberg, H. Sabharwal, S. Linse, I. Lazou, B. Lonnerdal, and C. Svanborg. 2000. A folding variant of alpha-lactalbumin with bactericidal activity against Streptococcus pneumoniae. Mol Microbiol 35:589.

P6. Svensson, M., A. Hakansson, A. K. Mossberg, S. Linse, and C. Svanborg. 2000. Conversion of alpha-lactalbumin to a protein inducing apoptosis. Proc Natl Acad Sci U S A 97:4221.

P7. Kohler, C., V. Gogvadze, A. Hakansson, C. Svanborg, S. Orrenius, and B. Zhivotovsky. 2001. A folding variant of human alpha-lactalbumin induces mitochondrial permeability transition in isolated mitochondria. Eur J Biochem 268:186.

P8. Svensson, M., A. K. Mossberg, J. Pettersson, S. Linse, and C. Svanborg. 2003. Lipids as cofactors in protein folding: stereo-specific lipid-protein interactions are required to form HAMLET (human alpha-lactalbumin made lethal to tumor cells). Protein Sci 12:2805.

P9. Svensson, M., J. Fast, A. K. Mossberg, C. Duringer, L. Gustafsson, O. Hallgren, C. L. Brooks, L. Berliner, S. Linse, and C. Svanborg. 2003. Alpha-lactalbumin unfolding is not sufficient to cause apoptosis, but is required for the conversion to HAMLET (human alpha-lactalbumin made lethal to tumor cells). Protein Sci 12:2794.

P10. Duringer, C., A. Hamiche, L. Gustafsson, H. Kimura, and C. Svanborg. 2003. HAMLET Interacts with Histones and Chromatin in Tumor Cell Nuclei. J Biol Chem 278:42131.

P11. Fischer, W., L. Gustafsson, A. K. Mossberg, J. Gronli, S. Mork, R. Bjerkvig, and C. Svanborg. 2004. Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival. Cancer Res 64:2105.

P12. Casbarra, A., L. Birolo, G. Infusini, F. Dal Piaz, M. Svensson, P. Pucci, C. Svanborg, and G. Marino. 2004. Conformational analysis of HAMLET, the folding variant of human alpha-lactalbumin associated with apoptosis. Protein Sci 13:1322.

P13. Baltzer, A., C. Svanborg, and R. Jaggi. 2004. Apoptotic cell death in the lactating mammary gland is enhanced by a folding variant of alpha-lactalbumin. Cell Mol Life Sci 61:1221.

P14. Gustafsson, L., I. Leijonhufvud, A. Aronsson, A. K. Mossberg, and C. Svanborg. 2004. Treatment of skin papillomas with topical alpha-lactalbumin-oleic acid. N Engl J Med 350:2663.

Reviews


R1. Svensson, M., C. Duringer, O. Hallgren, A. K. Mossberg, A. Hakansson, S. Linse, and C. Svanborg. 2002. Hamlet--a complex from human milk that induces apoptosis in tumor cells but spares healthy cells. Adv Exp Med Biol 503:125.

R2. Svanborg, C., H. Agerstam, A. Aronson, R. Bjerkvig, C. Duringer, W. Fischer, L. Gustafsson, O. Hallgren, I. Leijonhuvud, S. Linse, A. K. Mossberg, H. Nilsson, J. Pettersson, and M. Svensson. 2003. HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects. Adv Cancer Res 88:1.

R3. L. Gustafsson, C. Boiers, O. Hallgren, AK. Mossberg, J. Pettersson, W. Fischer, A. Aronsson, C. Svanborg. HAMLET kills tumor cells by apoptosis: structure, cellular mechanisms and therapy. (In press - Journal of Nutrition. October 2004)

R4. Düringer, C, Hallgren, O, Gustafsson, L, Petterson, J ,Mossberg, A, Manilov. T and Svanborg, C. HAMLET; a novel tool to identify apoptotic pathways in tumor cells. (In press - Application of Apoptosis to Cancer Treatment. October 2004)

Manuscripts


M1. Håkansson, A., M. Olsson, J. Wennerberg, H. Sabharwal, and C. Svanborg. Protection by a human milk protein complex against tumor development in nu/nu and syngeneic mice from. manuscript

M2. Håkansson, A., D. Briles, B. Zhivotovsky, S. Orrenius, and C. Svanborg. Cell death and DNA fragmentation induced by Streptococcus pneumniae in respitory epithelial cells. manuscript

M3. Hallgren, O., C. Düringer, L. Gustafsson, H. Irjala, C. Köhler, G. Selivanova, S. Orrenius and C. Svanborg. Tumor cell death in response to HAMLET is independent of Bcl-2 and P53. manuscript

M4. Düringer, C., A. Hamiche, A-K. Mossberg and C. Svanborg. HAMLET-histone interaction: Structural prerequisites and correlations to cell death activity. manuscript

M5. Pettersson, J., A.-K. Mossberg, S. Linse and C. Svanborg. Point mutations in the hinge region between the alpha-helical and beta-sheet domain in alpha-lactalbumin: Effect on folding and conversion to HAMLET. manuscript

M6. Pettersson, J., A.-K. Mossberg and C. Svanborg. Alpha-lactalbumin sequence variation influences the formation of HAMLET-like complexes. manuscript

M7. Wullt, B., A. Mossberg, and C. Svanborg. Intra-vesical instillation of HAMLET (Human alpha-lactalbumine made lethal to tumor cells) in patients with bladder cancer. manuscript

M8. Gustafsson, L., O. Hallgren, B. Spolaore, C. Robinson, C. Svanborg. HAMLET causes unfolded protein overload in tumor cells and triggers apoptosis through the proteasome. manuscript

 

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Updated by Babu Ahmad on March 14, 2005
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