A serine protein kinase, S6 kinase, is specific for the ribosomal protein S6 in 40S subunits. S6 kinase is activated by a variety of mitogenic agents. In vitro evidence suggests that phosphorylated S6 subunits are preferentially utilized in forming the initiation complex in protein synthesis. Also, S6 kinase activity is stimulated during maturation of Xenopus oocytes induced by progesterone or insulin. The mechanism of activation of S6 kinase in vivo is poorly understood. As the purification of S6 kinase has been difficult, a number of important questions concerning the activation of the protein, the regulation of mRNA expression, and the organization of the S6 kinase gene remain. Recently the cDNA for Xenopus S6 kinase was isolated. Using that cDNA as a probe, the human S6 kinase cDNA will be obtained. These cDNAs will be expressed in a Baculovirus expression vector system. Native and mutagenized proteins will be produced and questions concerning the activation and regulation of the enzyme will be addressed. Polyclonal and monoclonal antibodies against the proteins will be produced to aid in the characterization. The activation of S6 kinase is very rapid, suggesting the involvement of post-translational modifications. The level of induction and the half-life of mRNA will be determined in order to define parameters of transcriptional regulation of the gene. The transcription and potential processing of the mRNA will be studied with the idea of sorting out whether this kinase clone is part of a larger S6 kinase gene family. The genomic organization of the human kinase will be explored. The 5' and 3' regions of the gene will be examined to gain understanding of transcriptional regulation. The chromosomal localization of the gene will be determined by somatic cell hybrid analysis and in situ hybridization. Should the gene be localized to an area associated with chromosomal breakpoints or growth factors, more extensive mapping of the region will be undertaken to determine if gene amplification or rearrangement is present. AS S6 kinase is stimulated through many separate pathways it seems likely this enzyme is involved in disordered cell growth or differentiation. Its high degree of activity in lymphoid tissue suggest a role in lymphoid development. The high level of conservation across many species suggests a forefront role for this kinase in the control of cell growth. Abnormalities in this enzyme may be key to the understanding of such disease as childhood lymphoblastic leukemia.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Physician Scientist Award (K11)
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Special Emphasis Panel (SRC (05))
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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