FIG. 10.22

Can extracellular matrix proteins influence gene expression?

BACKGROUND The adhesion of cells to the extracellular matrix is required for cell division, DNA synthesis, and proper cell shape. Research by Iranian-American cell biologist Mina Bissell and colleagues indicated that a cell’s interaction with extracellular matrix proteins influences gene expression. Bissell discovered that mammary cells synthesize and secrete high levels of the milk protein β-casein when grown in a three-dimensional collagen matrix but not in a two-dimensional collagen matrix. American cell biologist Joan Caron followed up these studies using liver cells (hepatocytes).

HYPOTHESIS Caron hypothesized that a specific protein in the extracellular matrix is necessary for the expression of the protein albumin from hepatocytes grown in culture. Albumin is a major product of hepatocytes.

EXPERIMENT Caron cultured hepatocytes on a thin layer of type I collagen, which does not induce albumin synthesis. Next, she added a mixture of several different extracellular matrix proteins to the culture and looked for changes in albumin gene expression and protein secretion into the media. She then tested individual extracellular matrix proteins from the mixture to see which one was responsible for the increase in albumin gene expression.

RESULTS Caron found that when she cultured cells on collagen with a combination of three extracellular matrix proteins—laminin, type IV collagen, and heparin sulfate proteoglycan (HSPG)—the cells synthesized albumin mRNA and secreted albumin protein for several weeks, but if she cultured the cells on collagen alone, they did not (top and middle graphs). In addition, when she tested individual extracellular matrix proteins, she found that laminin, but not any of the other proteins, caused an increase in albumin gene expression (bottom graph).

CONCLUSION Caron’s hypothesis was supported by the experiments. A specific extracellular matrix protein, laminin, influences the expression of albumin by hepatocytes.

FOLLOW-UP WORK Bissell continued her work with mammary cells and found that the expression of the β-casein gene was also increased by laminin in the same way as the albumin gene in hepatocytes.

SOURCES Lee, E. Y., et al. 1985. “Interaction of Mouse Mammary Epithelial Cells with Collagen Substrata: Regulation of Casein Gene Expression and Secretion.” Proceedings of the National Academy of Sciences, USA 82:1419–1423; Caron, J. M. 1990. “Induction of Albumin Gene Transcription in Hepatocytes by Extracellular Matrix Proteins.” Molecular and Cellular Biology 10:1239–1243.