IKK2 Gene Essential for Liver Development

For this article, Jim Kling interviewed Inder M. Verma, professor of genetics at the Salk Institute for Biological Studies. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more than the average paper of the same type and age. Q.T. Li, D. Van Antwerp, F. Mercurio, K.F. Lee, I.M. Verma, "Severe liver degeneration in mice lacking the I kappa B kinase 2 gene," Science, 284:321-5, April 9, 1999. (Cited in 150 papers) Courtesy of Inder M. VermaInder M. Verma NF-kB, a central molecule in immune response regulation, growth, and development, switches on many of the genes involved with these vital processes. When inactive, NF-kB resides in the cell cytoplasm and is blocked by IkB proteins (IkBa and IkBa), which prevent it from entering the nucleus. NF-kB is released when a kinase complex phosphorylates the IkBas, causing them to relinquish their hold on NF-kB and allowing them to enter the nucleus and initiate transcription. The kinase complex contains two kinases, IKK1 and IKK2, which have identical activities with respect to IKKb IkB. In this paper, the authors, led by Qiutang Li, a postdoctoral fellow in the laboratory of Inder M. Verma, professor of genetics at the Salk Institute for Biological Studies, found that IKK2 is essential for liver development. The team started with IKK2 because IKK1 hadn't been cloned yet (it has since been1). "The question was, 'What is the role of each one of those kinases and what other roles might they play?'... not that we anticipated them to be that different," recalls Verma. In fact, they turned out to be very different. The team created IKK2 knockout mice. They found that between days 12-13 and 13-14 of the gestation period, the animals died of liver apoptosis, probably due to tumor necrosis factor aTNFa. Although the researchers could detect weak normal IKK1 activity, the results made it clear that IKK1 could not make up for the absence of IKK2. In subsequent studies, the team made IKK1 knockouts and found that the animals survived gestation, but their limbs never extended and the animals died soon after birth.2,3 Double knockouts died at day 9-12 of the gestation period, and the neural tube in the hindbrain failed to close in these animals. "For the first time, we showed that NF-kB might have an effect on neural development," says Verma. The numerous citations are due to the subject matter. "[These proteins] regulate NF-kB, which is in turn necessary for the activity of maybe hundreds of genes in the inflammatory response, all of those genes are turned on by NF-kB," says Verma. "Those people who are interested in the induction of genes involved in the immunomodulatory responses have to quote the paper." The differences among IKK1, IKK2, and double knockouts suggest that IKK1 and IKK2 have more substrates and play other biological roles. "There must be other substrates, and I think that's the big challenge. The phenotypes are so different, so the question comes up then, 'What else are they doing?' [and] 'Could there be other kinases [involved in NF-kB regulation]?' We just don't know." To answer those questions, Verma and his colleagues are using double knockout cells to see what proteins are phosphorylated in response to specific signals. The team is also using cDNA libraries with individual proteins expressed in bacterial cells and treating them with IKK1 and IKK2 to see which proteins get phosphorylated. "There is nothing to talk about yet, but both [lines of inquiry] are being pursued," says Verma. Jim Kling can be contacted at jkling@nasw.org. References 1. F. Mercurio et al., "IKK-1 and IKK-2: Cytokine-activated IkB kinases essential for NF-kB activation," Science, 278:860-6, 1997. 2. Q. Li et al., "Complete lack of NF-kB activity in IKK1 and IKK2 double deficient mice: Additional defect in neurulation," Genes and Development, 14[14]:1729-33, 2000. 3. Q. Li et al., "IKK1-deficient mice exhibit abnormal development of skin and skeleton," Genes and Development, 13[10],1322-8, 1999.

IKK2 Gene Essential for Liver Development

Interested in reading more?

Become a Member of