Accession Number : ADA321803

Title :   The Role of HAP Kinases in Breast Cancer.

Descriptive Note : Annual rept. 29 Aug 95-28 Aug 96,

Corporate Author : MASSACHUSETTS GENERAL HOSPITAL BOSTON

Personal Author(s) : Kyriakis, John M.

PDF Url : ADA321803

Report Date : SEP 1996

Pagination or Media Count : 23

Abstract : We are studying two complex signal transduction networks activated by stress and inflammatory cytokines (TNF): the SAPK and p38 pathways. The SAPKs are activated in situ by at least four MEKs including SEK1. p38 is activated by SEK1, MKK3 and MKK6. We are now characterizing elements upstream of these MEKs and have obtained the following results. Germinal center kinase (GCK) can potently activate the SAPKs and SEK1 in cotransfections. GCK interacts with the small GTPase Rab8. Optimal activation of the SAPKs by GCK in situ requires the C-terminal PEST motif. RIP, a kinase associated with the TNF receptor and Fas is a direct activator of MKK6. Finally SPRK and PAK1, two kinases upstream of the SAPKs can interact in situ. Our cell biological studies demonstrate that elements of the p38 pathway, including Cdc42Hs, SEK1, MKK3, MKK6 and p38 itself can each arrest cells at the G1/S checkpoint in the cell cycle. TNF can inhibit the growth of mammary cancer cells. Our data indicate that the components which we are identifying for the SAPK and p38 pathways may mediate this growth inhibition. An understanding of these molecular players will prove important to the development of novel anticancer drugs.

Descriptors :   *MAMMARY GLANDS, *PHOSPHORUS TRANSFERASES, *BREAST CANCER, ACTIVATION, OPTIMIZATION, BIOLOGY, PROTEINS, CYCLES, INHIBITION, CELLS(BIOLOGY), ANTIBIOTICS, GROWTH(PHYSIOLOGY).

Subject Categories : Biochemistry
      Medicine and Medical Research

Distribution Statement : APPROVED FOR PUBLIC RELEASE