PMID- 8175886
OWN - NLM
STAT- MEDLINE
DCOM- 19940603
LR  - 20190508
IS  - 0021-9525 (Print)
IS  - 1540-8140 (Electronic)
IS  - 0021-9525 (Linking)
VI  - 125
IP  - 3
DP  - 1994 May
TI  - Targeted expression of stromelysin-1 in mammary gland provides evidence for a 
      role of proteinases in branching morphogenesis and the requirement for an intact 
      basement membrane for tissue-specific gene expression.
PG  - 681-93
AB  - The extracellular matrix (ECM) is an important regulator of the differentiated 
      phenotype of mammary epithelial cells in culture. Despite the fact that 
      ECM-degrading enzymes have been implicated in morphogenesis and tissue 
      remodeling, there is little evidence for a direct role for such regulation in 
      vivo. We generated transgenic mice that express autoactivated isoforms of the 
      matrix metalloproteinase stromelysin-1, under the control of the whey acidic 
      protein gene promoter, to examine the effect of inappropriate expression of this 
      enzyme. Stromelysin-1 is implicated as the primary player in the loss of basement 
      membrane and loss of function in the mammary gland during involution. The 
      transgene was expressed at low levels in mammary glands of virgin female mice, 
      leading to an unexpected phenotype: The primary ducts had supernumerary branches 
      and showed precocious development of alveoli that expressed beta-casein at levels 
      similar to that of an early- to mid-pregnant gland. Lactating glands showed high 
      levels of transgene expression, with accumulation at the basement membrane, and a 
      decrease in laminin and collagen IV, resulting in a loss of basement membrane 
      integrity; this was accompanied by a dramatic alteration of alveolar morphology, 
      with decreased size and shrunken lumina containing little beta-casein. During 
      pregnancy, expression of endogenous whey acidic protein and beta-casein was 
      reduced in transgenic glands, confirming the observed dependence of milk protein 
      transcription of ECM in mammary epithelial cells in culture. These data provide 
      direct evidence that stromelysin-1 activity can be morphogenic for mammary 
      epithelial cells, inducing hyperproliferation and differentiation in virgin 
      animals, and that its lytic activity can, indeed, disrupt membrane integrity and 
      reduce mammary-specific function. We conclude that the balance of ECM-degrading 
      enzymes with their inhibitors, and the associated regulation of ECM structure, is 
      crucial for tissue-specific gene expression and morphogenesis in vivo.
FAU - Sympson, C J
AU  - Sympson CJ
AD  - Life Sciences Division, Lawrence Berkeley Laboratory, Berkeley, California 94720.
FAU - Talhouk, R S
AU  - Talhouk RS
FAU - Alexander, C M
AU  - Alexander CM
FAU - Chin, J R
AU  - Chin JR
FAU - Clift, S M
AU  - Clift SM
FAU - Bissell, M J
AU  - Bissell MJ
FAU - Werb, Z
AU  - Werb Z
LA  - eng
GR  - CA 57621/CA/NCI NIH HHS/United States
GR  - ES07106/ES/NIEHS NIH HHS/United States
GR  - HD 23539/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (Caseins)
RN  - 0 (DNA Primers)
RN  - 0 (Laminin)
RN  - 0 (Milk Proteins)
RN  - 0 (Whey Proteins)
RN  - 9007-34-5 (Collagen)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
EIN - J Cell Biol 1996 Feb;132(4):following 752
GS  - Cas
GS  - WAP
MH  - Animals
MH  - Base Sequence
MH  - Basement Membrane/ultrastructure
MH  - Caseins/genetics
MH  - Cell Differentiation
MH  - Collagen/genetics
MH  - DNA Primers/chemistry
MH  - Female
MH  - Gene Expression Regulation
MH  - Genes
MH  - Lactation
MH  - Laminin/genetics
MH  - Mammary Glands, Animal/*cytology/*enzymology
MH  - Matrix Metalloproteinase 3
MH  - Metalloendopeptidases/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Milk Proteins/genetics
MH  - Molecular Sequence Data
MH  - Morphogenesis
MH  - Pregnancy
MH  - Promoter Regions, Genetic
MH  - Restriction Mapping
MH  - Whey Proteins
PMC - PMC2119999
EDAT- 1994/05/01 00:00
MHDA- 1994/05/01 00:01
PMCR- 1994/11/01
CRDT- 1994/05/01 00:00
PHST- 1994/05/01 00:00 [pubmed]
PHST- 1994/05/01 00:01 [medline]
PHST- 1994/05/01 00:00 [entrez]
PHST- 1994/11/01 00:00 [pmc-release]
AID - 94230575 [pii]
AID - 10.1083/jcb.125.3.681 [doi]
PST - ppublish
SO  - J Cell Biol. 1994 May;125(3):681-93. doi: 10.1083/jcb.125.3.681.