PMID- 2103501
OWN - NLM
STAT- MEDLINE
DCOM- 19911004
LR  - 20071114
IS  - 1044-579X (Print)
IS  - 1044-579X (Linking)
VI  - 1
IP  - 4
DP  - 1990 Aug
TI  - Transforming growth factor alpha: expression, regulation and biological action of 
      its integral membrane precursor.
PG  - 265-75
AB  - Transforming growth factor alpha (TGF alpha) is a 6 kDa polypeptide mitogen that 
      interacts with the epidermal growth factor receptor and activates its intrinsic 
      tyrosine kinase. The mature 50 amino acid TGF alpha is released from a 159 or 160 
      amino acid integral membrane glycoprotein precursor, denoted proTGF alpha, via 
      cleavage at both termini by an unknown protease with elastase-like specificity. 
      Rat proTGF alpha is encoded by a 4.5 kb mRNA that is transcribed from a gene 
      containing 6 exons and spanning 85 kb of DNA. Expression of TGF alpha is most 
      prevalent and abundant in transformed cells and tumors, but also detectable at 
      modest levels in a limited number of normal cells and tissues. In many neoplastic 
      cells, proteolytic processing of proTGF alpha is incomplete and/or inefficient, 
      resulting in the preponderance of soluble and/or membrane-bound forms larger than 
      the mature TGF alpha. To characterize the biological activities of the 
      transmembrane TGF alpha precursor in the absence of processing, amino acid 
      substitutions were introduced at the cleavage sites by site-directed mutagenesis 
      of the rat TGF alpha cDNA. Fibroblasts expressing the mutant proTGF alpha 
      constructs did not secrete TGF alpha, but did accumulate proTGF alpha at the cell 
      surface. Coincubation of these cells with A431 cells resulted in binding and 
      autophosphorylation of EGF receptors, and mobilization of intracellular calcium 
      in A431 cells, demonstrating that the transmembrane proTGF alpha can activate EGF 
      receptors on adjacent cells, leading to signal transduction. In addition, rat 
      fibroblasts constitutively expressing the wild-type or mutant proTGF alpha became 
      morphologically transformed in culture, and induced tumors in nude mice. Thus, 
      the interaction between membrane-anchored ligand and receptor triggers 
      mitogenesis that can culminate in neoplastic transformation. To characterize the 
      physiological and pathological effects of TGF alpha in vivo, particularly with 
      respect to epithelial cells, transgenic mice were developed which overexpress the 
      growth factor in multiple or specific tissues. Widespread overexpression of TGF 
      alpha driven by the metallothionein promoter induced epithelial hyperplasia in 
      several organs, including liver and intestine, without disrupting normal tissue 
      architecture. In contrast, the pancreas displayed increased proliferation of both 
      acinar cells and fibroblasts, and focal alteration of acinar cell 
      differentiation. This pancreatic hyperplasia, fibroplasia, and metaplasia were 
      reproduced when TGF alpha expression was placed under control of the elastase 
      promoter, and thus locally restricted to acinar cells, suggesting autocrine 
      and/or paracrine mode of action. Finally, overexpression of TGF alpha promoted 
      neoplastic transformation of certain epithelia. In coagulation gland, there was 
      dramatic hyperplasia and dysplasia with focal evidence of carcinoma in 
      situ.(ABSTRACT TRUNCATED AT 400 WORDS)
FAU - Luetteke, N C
AU  - Luetteke NC
AD  - Lineberger Comprehensive Cancer Center, Chapel Hill, NC.
FAU - Lee, D C
AU  - Lee DC
LA  - eng
GR  - CA43793/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - England
TA  - Semin Cancer Biol
JT  - Seminars in cancer biology
JID - 9010218
RN  - 0 (Protein Precursors)
RN  - 0 (Transforming Growth Factor alpha)
RN  - 0 (protransforming growth factor alpha)
SB  - IM
GS  - TGF&agr;
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Membrane/metabolism
MH  - Gene Expression/physiology
MH  - Humans
MH  - Molecular Sequence Data
MH  - Protein Precursors/*physiology
MH  - Transforming Growth Factor alpha/genetics/*physiology
RF  - 62
EDAT- 1990/08/01 00:00
MHDA- 1990/08/01 00:01
CRDT- 1990/08/01 00:00
PHST- 1990/08/01 00:00 [pubmed]
PHST- 1990/08/01 00:01 [medline]
PHST- 1990/08/01 00:00 [entrez]
PST - ppublish
SO  - Semin Cancer Biol. 1990 Aug;1(4):265-75.