ORIGINAL ARTICLE

Cell Research (2007): 151-162
© 2007 IBCB, SIBS, CAS All rights reserved 1001-0602/06 $ 30.00
www.nature.com/cr

Anti-apoptotic effect of retinoic acid on retinal progenitor cells mediated by a protein kinase A-dependent mechanism

Roman Kholodenko¹, Irina Kholodenko¹, Viktor Sorokin², Anna Tolmazova¹, Olga Sazonova¹, Anton Buzdin¹

Correspondence: Anton Buzdin Tel: +7-495-330-6574; Fax: +7-495-330-6538 E-mail: anton@humgen.siobc.ras.ru

Download as printable (PDF) file Full Text (html)file Search Medline for articles by: Roman Kholodenko

Retinal progenitor cells (RPCs) are neural stem cells able to differentiate into any normal adult retinal cell type, except for pigment epithelial cells. Retinoic acid (RA) is a powerful growth/differentiation factor that generally causes growth inhibition, differentiation and/or apoptosis. In this study, we demonstrate that RA not only affects mouse RPC differentiation but also improves cell survival by reducing spontaneous apoptotic rate without affecting RPC proliferation. The enhanced cell survival was accompanied by a significant upregulation of the expression of protein kinase A (PKA) and several protein kinase C (PKC) isoforms. Treatment of cells grown in RA-free media with 8-bromoadenosine3',5'-cyclic monophosphate, a known activator of PKA, resulted in an anti-apoptotic effect similar to that caused by RA; whereas the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride led to a significant (~32%) increase in apoptosis. In contrast, treatment of RPCs with any of two PKC selective inhibitors, 2,2',3,3',4,4'-hexahydroxy-1,1'-biphenyl-6,6'-dimethanol dimethyl ether and bisindolylmaleimide XI, led to diminished apoptosis; while a PKC activator, phorbol 12-myristate 13-acetate, increased apoptosis. These and other data suggest that the effect of RA on RPC survival is mostly due to the increased anti-apoptotic activity elicited by PKA, which might in turn be antagonized by PKC. Such a mechanism is a new example of tight regulation of important biological processes triggered by RA. Although the detailed mechanisms remain to be elucidated, we provide evidence that the pro-survival effect of RA on RPCs is not mediated by changed expression of p53 or bcl-2, and appears to be independent of β-amyloid, Fas ligand, TNF-α, ganglioside GM1 and ceramide C16-induced apoptotic pathways.

Cell Research (2007) 17:151-162. doi: 10.1038/sj.cr.7310147; published online 13 February 2007

Keywords: retinal progenitor cells, apoptosis, retinoic acid, protein kinase A, protein kinase C