Accession Number : ADA299332

Title :   Regulation of a Kinase Cascade Involved in Cancer and Normal Cell Growth.

Descriptive Note : Annual rept. 1 Jun 94-31 May 95,

Corporate Author : CASE WESTERN RESERVE UNIV CLEVELAND OH

Personal Author(s) : Templeton, Dennis J. ; Yan, Minhong

PDF Url : ADA299332

Report Date : 01 JUL 1995

Pagination or Media Count : 22

Abstract : We have identified serine 218 and serine 222 whose phosphorylations are critical for MEK activation both in vitro and in vivo. Interestingly, these two serine residues are differentially phosphorylated by Raf-1 and MEKK: Raf-1 phosphorylate serine 218 and serine 222 equally while MEKK preferentially phosphorylated serine 218. In an attempt to study the potential of MEKK as an oncogene, we found that truncation of the putative N-terminal regulatory domain of MEKK failed to transform different cells. Instead stable overexpression of DMEKK appeared to be either lethal to growth inhibitory. To overcome the problem associated with constitutive overexpression of DMEKK, an inducible expression system was applied. Surprisingly, inducible expression of DMEKK had no effect on mapk activation in NIH3T3 cells whose MAPK pathways were still functional. Moreover we found that the recently discovered SAPK pathway was activated by DMEKK induction. Finally, in collaboration with other laboratories, we demonstrated that MEKK can directly phosphorylate and activate the SAPK activator SEK in vivo and in vitro. Therefore MEKK--SEK--SAPK defines a novel kinase cascade distinct from the Raf-l-- MEK--MAPK kinase cascade.

Descriptors :   *GROWTH(GENERAL), *IN VITRO ANALYSIS, *IN VIVO ANALYSIS, *CELLS(BIOLOGY), *CANCER, ACTIVATION, LETHALITY, RESIDUES, SERINE.

Subject Categories : Medicine and Medical Research
      Anatomy and Physiology

Distribution Statement : APPROVED FOR PUBLIC RELEASE