Mechanisms through which Rat Mammary Gland Carcinogenesis is Preferentially Initiated by H-Ras over K-Ras Signaling Pathways
Annual rept. 1 Jul 1998-30 Jun 1999
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This research distinguishes mechanisms through which activated Ras initiates rat mammary gland carcinogenesis. The initial experiment expressing H-Ras and K-Ras chimeric proteins in rat mammary gland Aim IA supports the hypothesis of Aim 1 the difference in rat mammary gland carcinogenesis results from differences in the last 20 amino acids of H-Ras and K-Ras. However, early results of the repeat experiment are beginning to weaken the hypothesis it is still to soon to tell. Aim 2A, expressing individual Ras effector loop mutants ELMs, which target particular Ras effectors, substantially weakens the hypothesis of Aim 2 No individual Ras effector will initiate transformation, rather multiple effectors must synergise Each of the Ras ELMs G37 activates RalGDS, E38 activates Raf, and C40 activates PI3K, individually causes tumors. The results of Aim lB, expression of Raf activated by fusion with Ras membrane localization signals Raf-Caax, contrast surprisingly with results from Aim 2A. None of the forms of Raf tested resulted in a single tumor, yet E38-Ras, which activates Raf, is very tumorgenic. These results suggest Raf-Caax is defective for in situ tumor formation, or that E38 Ras is activating an additional effector pathways.
- Anatomy and Physiology
- Medicine and Medical Research