Regulation of epithelial cell proliferation by transforming growth factors

✍ Scribed by Charles C. Bascom; Nancy J. Sipes; Robert J. Coffey; Harold L. Moses

• Publisher: John Wiley and Sons
• Year: 1989
• Tongue: English
• Weight: 543 KB
• Volume: 39
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.240390104

✦ Synopsis

The autocrine hypothesis of neoplastic transformation originally stated that transformed cells escaped normal growth restraints by the production of and autostimulation by endogenous growth factors. This hypothesis followed the demonstration by DeLarco and Todaro [l] that murine sarcoma virus-transformed 3T3 cells produced a factor that was capable of reversibly inducing soft agar growth in anchoragedependent target cells. The factor responsible for stimulating anchorage-independent growth was termed sarcoma growth factor (SGF); SGF preparations were later shown to consist of two separate molecules, transforming growth factors a and P (TGFa and TGFP) [2]. The hypothesis, therefore, was that TGFs would be found only in malignant cells; however, recent evidence suggests that TGFa and TGFP play important roles in normal growth and development. TGFa and TGFP are unrelated molecules whose actions are quite distinct. TGFa is a potent mitogen, while TGFP is inhibitory for most cells examined. A clear example of the normal growth regulatory roles of TGFa and TGFP is seen in both human and murine keratinocytes.

TGFa

TGFa was originally purified by Marquardt et al. [3] and is a 5,600-daltOn polypeptide that has sequence and significant structural homology to epidermal growth factor (EGF). Sequence data determined that TGFa is synthesized as a 160-amino acid precursor that is processed in a complex manner to yield the active molecule [4, 51. TGFa binds to the EGF receptor and appears to mediate its biological activity through this interaction. When assayed in cell culture systems, the biological activities of TGFa and EGF are virtually identical. However, some in vivo and organ culture assays indicate quantitative, but not qualitative, differences between TGFa and EGF TGFa was originally isolated from conditioned medium of virally transformed 3T3 cells [ 11 and later from the conditioned medium of human carcinoma cells [7].