Autocrine nerve growth factor protects human keratinocytes from apoptosis through its high affinity receptor (TRK): A role for BCL-2

被引:86
作者
Pincelli, C
Haake, AR
Benassi, L
Grassilli, E
Magnoni, C
Ottani, D
Polakowska, R
Franceschi, C
Giannetti, A
机构
[1] UNIV MODENA, DEPT BIOMED SCI, SECT GEN PATHOL, I-41100 MODENA, ITALY
[2] UNIV ROCHESTER, DEPT DERMATOL, ROCHESTER, NY 14627 USA
关键词
HaCat cells; K252; programmed cell death;
D O I
10.1111/1523-1747.ep12340768
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
Normal human keratinocytes synthesize and release nerve growth factor (NGF) and express both the low-and the high-affinity NGF receptor, Because NGF has been shown to rescue certain cell types from programmed cell death, we investigated the role of endogenous NGF in preventing keratinocyte apoptosis, We report here that apoptosis is induced in normal human keratinocytes in culture by blocking endogenous NGF signaling with either anti-NGF neutralizing antibody or K252, a specific inhibitor of the tyrosine kinase high-affinity NGF receptor. Apoptosis was assessed by DNA laddering, electron microscopy, and in situ nick end labeling technique, In anti-NGF-treated keratinocytes, the apoptotic process starts at 96 h, and is maximal at 120 h. After K252 treatment, apoptosis starts at 48 h and peaks at 120 h, Because the product of the bcl-2 proto-oncogene protects many cell types from apoptosis, we measured the levels of this protein in apoptotic keratinocytes, We found that both K252 and anti-NGF antibody strikingly downregulate bcl-2 expression, starting at 72 h. Furthermore, HaCat keratinocytes stably transfected with a plasmid containing bcl-2 cDNA fail to undergo apoptosis when treated with K252. These findings show that autocrine NGF acts as a survival factor for human keratinocytes in vitro through its high-affinity NGF receptor, possibly by maintaining constant levels of Bcl-2.
引用
收藏
页码:757 / 764
页数:8
相关论文
共 68 条
[31]   BCL2 PROTEIN IS TOPOGRAPHICALLY RESTRICTED IN TISSUES CHARACTERIZED BY APOPTOTIC CELL-DEATH [J].
HOCKENBERY, DM ;
ZUTTER, M ;
HICKEY, W ;
NAHM, M ;
KORSMEYER, SJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (16) :6961-6965
[32]   EXPRESSION AND STRUCTURE OF THE HUMAN NGF RECEPTOR [J].
JOHNSON, D ;
LANAHAN, A ;
BUCK, CR ;
SEHGAL, A ;
MORGAN, C ;
MERCER, E ;
BOTHWELL, M ;
CHAO, M .
CELL, 1986, 47 (04) :545-554
[33]   BCL-2 INHIBITION OF NEURAL DEATH - DECREASED GENERATION OF REACTIVE OXYGEN SPECIES [J].
KANE, DJ ;
SARAFIAN, TA ;
ANTON, R ;
HAHN, H ;
GRALLA, EB ;
VALENTINE, JS ;
ORD, T ;
BREDESEN, DE .
SCIENCE, 1993, 262 (5137) :1274-1277
[34]   NERVE GROWTH-FACTOR SUPPRESSES APOPTOSIS OF MURINE NEUTROPHILS [J].
KANNAN, Y ;
USAMI, K ;
OKADA, M ;
SHIMIZU, S ;
MATSUDA, H .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1992, 186 (02) :1050-1056
[35]   TYROSINE PHOSPHORYLATION AND TYROSINE KINASE-ACTIVITY OF THE TRK PROTOONCOGENE PRODUCT INDUCED BY NGF [J].
KAPLAN, DR ;
MARTINZANCA, D ;
PARADA, LF .
NATURE, 1991, 350 (6314) :158-160
[36]   THE TRK PROTOONCOGENE PRODUCT - A SIGNAL TRANSDUCING RECEPTOR FOR NERVE GROWTH-FACTOR [J].
KAPLAN, DR ;
HEMPSTEAD, BL ;
MARTINZANCA, D ;
CHAO, MV ;
PARADA, LF .
SCIENCE, 1991, 252 (5005) :554-558
[37]   K-252 COMPOUNDS, NOVEL AND POTENT INHIBITORS OF PROTEIN-KINASE-C AND CYCLIC NUCLEOTIDE-DEPENDENT PROTEIN-KINASES [J].
KASE, H ;
IWAHASHI, K ;
NAKANISHI, S ;
MATSUDA, Y ;
YAMADA, K ;
TAKAHASHI, M ;
MURAKATA, C ;
SATO, A ;
KANEKO, M .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1987, 142 (02) :436-440
[38]   APOPTOSIS - BASIC BIOLOGICAL PHENOMENON WITH WIDE-RANGING IMPLICATIONS IN TISSUE KINETICS [J].
KERR, JFR ;
WYLLIE, AH ;
CURRIE, AR .
BRITISH JOURNAL OF CANCER, 1972, 26 (04) :239-+
[39]  
KOIZUMI S, 1988, J NEUROSCI, V8, P715
[40]   ACTIVATION OF PROGRAMMED CELL-DEATH IN THE RAT VENTRAL PROSTATE AFTER CASTRATION [J].
KYPRIANOU, N ;
ISAACS, JT .
ENDOCRINOLOGY, 1988, 122 (02) :552-562