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The Story of Bcl-2 Linking cell apoptosis to tumor metastasis Crystal structure of Bcl-2 complex By Yaming Wang
Immunofluorescence stain of B cells in the spleen (green= Bcl-2) History • Bcl-2 was first isolated in B Cell Lymphoma cells • Caused by malignant B lymphocytes • Contributes about 85% of known types of lymphoma in US
History continued • The mutation of Bcl-2 was due to chromosome translocation • Very similar to the story of Cyclin D as an oncogene
Mistake happens during BCR (VDJ) rearrangement • Bcl-2 gene (from chromosome 14) is placed next to Ig heavy chain locus on chromosome 18 • This leads to the overexpression of Bcl-2 in B cells
But what is the mechanism that makes Bcl-2 a killer? Bcl family proteins govern programmed cell death (apoptosis)
Bcl-2 protein Biochemistry • Bcl-2 is a small protein (~29KD) • Bcl family proteins play crucial role in cell apoptosis • Divided into pro-survival and pro-apoptosis and usually balance each other out in healthy cells • Bcl-2 is a pro-survival protein and it protects cell from a wide range of cytotoxic insults, including cytokine deprivation, UV and -irradiation
Highly conserved BH domains • Bcl family proteins share highly conserved regions called Bcl homology (BH) domain • Structurally, divided into 3 families • BH3-only family proteins bind to pro-survival family proteins at the groove formed by BH1, BH2, and BH3 domains • Binding triggers the switch of apoptosis signaling
Bcl proteins are highly regulated • In response to different signal (ie. Death, or proliferation), Bcl family proteins are up/ down regulated. • Example: Regulation of T lymphocytes
In response to the immunosuppression signal, Bcl-XL level is down regulated. Yaming Wang, unpublished data, Microbiology and Immunology, 2006
What happen if Bcl-2 is over expressed or knocked out in mice? • Bcl-2 over expressing mice: • B cell lymphomas are frequently found • Bcl-2 knock out mice: • Viable but show growth retardation • Severe polycystic kidney disease • Massive apoptotic involution in thymus and spleen
Linking anti-apoptosis to tumor metastasis • Bcl-2 is also over expressed in many cancers including lung, colorectal, prostate, and breast, as well as in leukemia and other lymphomas
Alberts et al. Fig. 24-16 • Several changes are required • Eg. they have to lose their dependence to local growth factors, ability to survive without integrin signals • All these changes normally lead to cell apoptosis • Overcome by overexpressing pro-survival Bcl family proteins
Recent studies have shown that prolonged cell survival induced by the overexpression of Bcl-2 protein promotes the metastasis of many cancer cells such as melanoma cells and mammary epithelial cells. • Therefore, it maks Bcl protein a very good target for cancer therapy.
References • The lymphoma information network. http://www.LymphomaInfo.net/ • Veis D.J., Sorenson C.M., Bcl-2-deficient mice demostrate fulminant lymphod apoptosis, polycystic kidneys, and hypopigmented hiar, Cell, 75, 2, 1993 229-240 • Pinkas J., Martin S.S., Bcl-2-mediated cell survival promotes metastasis of EpH4 BMEKDD mammary epithelial cells, Mol Cancer Res; 2(10), 2004 • Anderson M.H., Svane I.M., Immunogenicity of Bcl-2 in patients with cancer, Blood, 105, 2, 2005 • Takaoka A., Adachi M., Anti-cell death activity protomtes pulmonary metastasis of melanoma cells, Oncogen, 14, 1997, 2971-2977 • Cory S., Adams J.M., The Bcl-2 family: regulators of the cellular life-or-death switch, Nature, 2, 2002, 647-656
Cancer therapies targeting Bcl-2 over expression • Some drugs that inhibit Bcl-2 by BH3 mimetics • Antisense oligonucleotide (inhibit mRNA translation) • More interestingly, shown that Bcl-2 over expression is in fact immunogenic. (meaning we can generate immunity against cells in which Bcl-2 is over expressed. ie. cancer cells.) • This gives us a way to target cancer cells using the weapons in our body (immune system) without harming healthy cells in cancer therapy.