Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo.
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.
Krajewski
S
S
La Jolla Cancer Research Foundation, Cancer Research Center, CA 92037, USA.
Bodrug
S
S
Krajewska
M
M
Shabaik
A
A
Gascoyne
R
R
Berean
K
K
Reed
J C
JC
D017209:Apoptosis / Q000502:physiology; D015152:Blotting, Northern; D002319:Cardiovascular System / Q000737:chemistry; D004064:Digestive System / Q000737:chemistry; D006413:Hematopoietic System / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008168:Lung / Q000737:chemistry; D008208:Lymphatic System / Q000737:chemistry; D009141:Musculoskeletal System / Q000737:chemistry; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000032:analysis* / Q000235:genetics; D009490:Neurosecretory Systems / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000737:chemistry*; D014566:Urogenital System / Q000737:chemistry
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger