Protein Responsible for Contact Inhibition Lacking in Skin Cancer Cells

Loss of the tumor suppressing protein alpha-E (alpha-epithelial) catenin triggers a complex series of molecular events that ultimately result in the development of skin squamous-cell carcinoma.

The adhesion protein alpha-E catenin has been implicated in limiting epithelial cell proliferation under conditions of high cell density (a process called contact inhibition of cell proliferation). To better study the role of this protein, investigators at Fred Hutchinson Cancer Research Center (Seattle, WA, USA) genetically engineered a line of mice that lacked the gene for alpha-E catenin in their hair follicle stem cells.

They reported in the May 24, 2011, issue of the journal Science Signaling that these animals developed squamous cell carcinomas, thus providing genetic evidence that alpha-E-catenin was a tumor suppressor. The investigators identified the transcriptional coactivator Yap1 as a protein that interacted with alpha-E-catenin. This interaction inhibited the activity of Yap1 and prevented Yap1 from translocating to the nucleus. Yap1 was also a target for the Hippo signaling pathway, which restricts cell proliferation and organ size by blocking the nuclear translocation of Yap1.

In human squamous cell carcinoma tumors, alpha-E-catenin abundance was inversely correlated with Yap1 activation. Thus, alpha-E-catenin may exert its tumor-suppressive effects by sequestering Yap1 and thereby limiting its activity.

"The fact that alpha-catenin-deficient mice developed skin cancer led us to conclude that the loss of this protein is an important event in cancer development, and that alpha-catenin functions as a tumor suppressor," said senior author Dr. Valeri Vasioukhin, associate professor human biology at Fred Hutchinson Cancer Research Center. "We also found that unlike normal cells, alpha-catenin-mutant cells cannot stop dividing when they become very crowded in the Petri dish – this characteristic is one of the hallmarks of cancer cells."

"We found that alpha-catenin controls cell proliferation by regulating Yap1, which is active in cells missing alpha-catenin. Therefore, Yap1 is likely to be an excellent target for the treatment of patients with squamous cell carcinoma," said Dr. Vasioukhin.

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Fred Hutchinson Cancer Research Center