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American Journal of Pathology, Vol 146, 1309-1319, Copyright © 1995 by American Society for Investigative Pathology
REGULAR ARTICLES |
S Krajewski, S Bodrug, M Krajewska, A Shabaik, R Gascoyne, K Berean and JC Reed
La Jolla Cancer Research Foundation, Cancer Research Center, CA 92037, USA.
The mcl-1 gene encodes an approximately 37-kd protein that has significant homology with Bcl-2, an inhibitor of programmed cell death that is expressed in many types of long-lived cells. In this study we determined the in vivo patterns of Mcl-1 protein production in normal human tissues by immunohistochemical means, using specific polyclonal antisera, and made comparisons with Bcl-2. Like Bcl-2, Mcl-1 immunostaining was observed in epithelial cells in a variety of tissues, including prostate, breast, endometrium, epidermis, stomach, intestine, colon, and respiratory tract. However, often the expression of mcl-1 and bcl-2 in complex epithelia occurred in gradients with opposing directions, such that Bcl-2 immunostaining tended to be higher in the less differentiated cells lining the basement membrane, whereas Mcl-1 immunostaining was more intense in the differentiated cells located in the upper layers of these epithelia. The in vivo patterns of mcl-1 and bcl-2 expression were also strikingly different in several other tissues as well. Within the secondary follicles of lymph nodes and tonsils, for example, germinal center lymphocytes were Mcl-1 positive but mostly lacked Bcl-2; whereas mantle zone lymphocytes expressed bcl-2 but not mcl-1. Intense Mcl-1 immunoreactivity was also detected in several types of neuroendocrine cells, including the adrenal cortical cells that are Bcl-2 negative, sympathetic neurons that also contain Bcl-2, a subpopulation of cells in the pancreatic islets, Leydig cells of the testis, and granulosa lutein cells of the ovarian corpus luteum but not in thyroid epithelium, which is strongly Bcl-2 positive. Little or no Mcl-1 was detected in neurons in the brain and spinal cord, in contrast to Bcl-2, which is present in several types of central nervous system neurons. Conversely, strong Mcl-1 immunostaining was found in cardiac and skeletal muscle, which contain comparatively less Bcl-2. Additional types of cells that are Bcl-2- negative but that expressed mcl-1 include chondrocytes and hepatocytes. These findings demonstrate that mcl-1 expression is widespread in vivo and imply that the Mcl-1 and Bcl-2 proteins fulfill different roles in the overall physiology of cell death regulation.
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S. H. Kaufmann, J. E. Karp, P. A. Svingen, S. Krajewski, P. J. Burke, S. D. Gore, and J. C. Reed Elevated Expression of the Apoptotic Regulator Mcl-1 at the Time of Leukemic Relapse Blood, February 1, 1998; 91(3): 991 - 1000. [Abstract] [Full Text] [PDF]
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N. K. Ossina, A. Cannas, V. C. Powers, P. A. Fitzpatrick, J. D. Knight, J. R. Gilbert, E. M. Shekhtman, L. D. Tomei, S. R. Umansky, and M. C. Kiefer Interferon-gamma Modulates a p53-independent Apoptotic Pathway and Apoptosis-related Gene Expression J. Biol. Chem., June 27, 1997; 272(26): 16351 - 16357. [Abstract] [Full Text] [PDF]
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J. Lomo, H. K. Blomhoff, S. E. Jacobsen, S. Krajewski, J. C. Reed, and E. B. Smeland Interleukin-13 in Combination With CD40 Ligand Potently Inhibits Apoptosis in Human B Lymphocytes: Upregulation of Bcl-xL and Mcl-1 Blood, June 15, 1997; 89(12): 4415 - 4424. [Abstract] [Full Text] [PDF]
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C.-F. Wu, N. H. Bishopric, and R. E. Pratt Atrial Natriuretic Peptide Induces Apoptosis in Neonatal Rat Cardiac Myocytes J. Biol. Chem., June 6, 1997; 272(23): 14860 - 14866. [Abstract] [Full Text] [PDF]
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P. Zhou, L. Qian, K. M. Kozopas, and R. W. Craig Mcl-1, a Bcl-2 Family Member, Delays the Death of Hematopoietic Cells Under a Variety of Apoptosis-Inducing Conditions Blood, January 15, 1997; 89(2): 630 - 643. [Abstract] [Full Text] [PDF]
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