Different Mechanisms of Protective and Differentiative Activities of Homological Peptides TGENHR and TQVEHR

S. S. Zhokhov¹, I. A. Kostanyan^1*, N. V. Gibanova¹, E. A. Surina¹, I. L. Rodionov², Z. I. Storozheva³, A. T. Proshin³, I. I. Babichenko⁴, and V. M. Lipkin¹

¹Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia; fax: (7-095) 336-6166; E-mail: iakost@mail.ibch.ru

²Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Pushchino 142290, Moscow Region, Russia; fax: (7-0967) 73-1780; E-mail: rodionov@fibkh.serpukhov.su

³Anokhin Institute of Normal Physiology, Russian Academy of Medical Sciences, ul. Mokhovaya 14, Moscow 103009, Russia; fax: (7-095) 203-5432; E-mail: proshin_at@mail.ru

⁴University of People's Friendship, ul. Miklukho-Maklaya 6, Moscow 117198, Russia; fax: (7-095) 433-2764; E-mail: babichenko@med.pfu.edu.ru

^* To whom correspondence should be addressed.

Received September 1, 2003; Revision received January 4, 2004

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Previously we identified a six-membered fragment ³⁵⁴TQVEHR³⁵⁹ of the C-terminal part of the PEDF (Pigment Epithelium-Derived Factor) differentiation factor molecule that shares homology with fragment ⁴¹TGENHR⁴⁶ of the HLDF (Human Leukemia Differentiation Factor) differentiation factor molecule, which is responsible for its differentiation activity. HLDF has been isolated from the culture medium of human promyelocytic leukemia cell line HL-60. Hexapeptides HLDF-6 (TGENHR) and PEDF-6 (TQVEHR) corresponding to these HLDF and PEDF molecule fragments, which were previously shown to induce cell differentiation (Kostanyan et al. (2000) Russian Journal of Bioorganic Chemistry, 26, 505-511), also have neuroprotective properties. Both peptides prevent degeneration of Purkinje cells of rat cerebellar vermis upon chemical hypoxia induced by sodium azide in vivo; this effect is also observed on a behavioral level. Peptide HLDF-6 but not PEDF-6 promotes survival of HL-60 cells upon chemical hypoxia. Peptides HLDF-6 and PEDF-6 affect different second messenger biosynthesis systems in HL-60 cells. HLDF-6 diminishes cyclic AMP level in those cells due to adenylate cyclase inhibition, while PEDF-6 inhibits phosphatidylinositol-specific phospholipase C stimulated by aluminum tetrafluoride anions.

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KEY WORDS: HLDF, PEDF, peptide, protective activity, chemical hypoxia, cerebellum, HL-60 cell line, adenylate cyclase, phosphatidylinositol-specific phospholipase C

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