Biochemistry & Molecular Biology, Howard Hughes Medical Institute
Cdk inhibitors: on the threshold of cell cycle control and development
Drs. Elledge and Jeffrey Wade Harper were recognized for their research on the mechanisms by which the cell regulates its division cycle. Loss of the cell’s ability to regulate its division is a critical step in the development of cancer. By synergistically merging the tools of genetics and biochemistry, Drs. Elledge and Harper isolated and characterized a human gene, CIP1, that encodes a critical negative regulator of the cell cycle. CIP1 binds and inhibits a class of protein kinases (cyclin-dependent kinases [Cdks]) that are required for the G1/S transition, the rate-limiting step in cell proliferation. CIP1 is transcriptionally regulated by the tumor suppressor p53. Mutations in p53 are the most commonly found lesion in human tumors, being present in more than 50% of all carcinomas.
The discovery by Drs. Elledge and Harper that p53 regulates an inhibitor of Cdks provided, for the first time, a mechanistic explanation of how this tumor suppressor protein negatively regulates the cell cycle. The fact that mutations in p53 are the most common lesion in human carcinomas indicates that loss of the CIP1 pathway is a critical determinant in tumorigenesis.
Drs. Elledge and Harper’s nomination was based on the following publications:
Dulic V, Kaufmann WK, Wilson SJ, Tlsty TD, Lees E, Harper JW, Elledge SJ, Reed SI. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest.
Cell. 1994 Mar 25;76(6):1013-23.
Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805-16.
Mechanism of regulated protein stability; discovery of SCF ubiquitin ligase pathway
Drs. Elledge and Jeffrey Wade Harper received the award for their seminal studies on the fundamental mechanism of regulated protein proteolysis. Through analysis of the pathways that control the destruction of cyclins and cyclin-dependent kinase inhibitors, they have discovered a modular ubiquitin ligase system, the SCF ubiquitin ligase, which is responsible for the regulated destruction of hundreds and possibly thousands of proteins. Mutations in components of these systems are implicated in cancer and developmental abnormalities. Moreover, there are multiple examples in which viruses such as HIV have co-opted these ubiquitin ligase pathways in order to subvert normal control mechanisms in the cell.
Dr. Elledge and Harper’s nomination was based on the following publications:
Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell. 1997 Oct 17;91(2):209-19.
Skowyra D, Koepp DM, Kamura T, Conrad MN, Conaway RC, Conaway JW, Elledge SJ, Harper JW. Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1.Science. 1999 Apr 23;284(5414):662-5.
Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW. The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev. 1999 Feb 1;13(3):270-83.