News Release

Tob or Not To Be: Role of tob gene in cancer investigated

Peer-Reviewed Publication

Cold Spring Harbor Laboratory

A collaboration of Japanese scientists are gaining important new insight into the function of the tob gene, and shedding new light on its role in human cancer. Their report is published in the May 15th issue of Genes & Development.

The tob gene is a member of a family of antiproliferative genes, whose encoded proteins prevent cell proliferation by constraining the cell growth cycle. Prompted, in part, by the finding that tob mRNA (messenger RNA; the nucleic acid intermediate that is used to synthesize a protein) is often decreased in human cancers, Dr. Tadashi Yamamoto and colleagues generated tob-deficient mice (tob knockout mice) to determine the function of the gene.

As Dr. Yamamoto explains, "The paper strongly argues that tob is a newly characterized tumor suppressor and that loss of its expression is relevant to development of human cancer."

Early on, the only abnormality that tob-deficient mice displayed was a decrease in bone density. However, by 18 months of age, Dr. Yamamoto and colleagues noted that tob-deficient mice were almost five times more likely to develop tumors than wild-type (genetically normal) mice.

tob-deficient mice developed a variety of spontaneous tumors, including those of liver, lung, and lymph node origin. In fact, ~60% of tob-deficient mice developed liver cancer. This finding was of particular interest because, at present, there are no mouse models of increased liver cancer susceptibility.

To investigate the potential utility of tob-deficient mice to model liver cancer, Dr. Yamamoto and colleagues treated tob-deficient mice with the liver-specific carcinogen, DEN. Exposure to DEN further increased the rate of liver tumor formation in tob-deficient mice, confirming that tob-deficient mice are markedly more susceptible to liver cancer than normal mice.

Dr. Yamamoto and colleagues also probed the effect of p53 loss on tumor formation in tob-deficient mice. p53 acts as a critical regulator of cell survival ,with more than half of all human cancers showing either absence of the p53 protein or mutations in the p53 gene. The researchers generated a strain of mice lacking both tob and p53 (tob/p53 double knockout mice). These tob/p53 double knockout mice displayed increased tumor incidence relative to mice only lacking tob, suggesting that tob and p53 may act synergistically to prevent tumor growth.

To gain molecular insight into how tob suppresses tumorigenesis, Dr. Yamamoto and colleagues used microarray analysis to examine the expression levels of ~500 cancer-related genes under conditions of tob under- and over-expression. cyclin D1, whose expression drives cells through the cell growth cycle, was one gene that appeared to be regulated by tob. Further work by Dr. Yamamoto and colleagues revealed that tob acts in conjunction with other factors to repress transcription of the cyclin D1 gene. When tob activity is diminished, Cyclin D1 levels rise, and cells progress through the cell cycle – consistent with their original finding of decreased tob mRNA levels in human cancers.

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