Humanin delays apoptosis in K562 cells by downregulation of P38 MAP kinase
Humanin (HN) is a newly identified neuroprotective peptide. In this study, we investigated its antiapoptotic effect and the potential mechanisms in K562 cells. Upon serum deprivation, expression of HN in K562 cells decreased and its intracellular distribution changed from cytoplasm to cell membrane. In HN stably transfected K562 cells, apoptosis was delayed compared with control vector transfected cells as measured by flow cytometry. Furthermore, analysis of different mitogen-activated protein (MAP) kinases activity revealed that extracellular signal-regulated kinase (ERK) pathway was inhibited while p38 signaling was activated following serum deprivation in K562 cells. And in HN transfected K562 cells, ERK downregulation was not affected, but p38 activation was suppressed, which may responsible for the delayed apoptosis in these cells. Activation of the ERK signaling pathway by phorbol myristate 13-acetate (PMA) and sorbitol protected K562 cells from serum deprivation induced apoptosis. Additionally, overexpression of HN reduced megakaryocytic differentiation of K562 cells. The present data outline the role of ERK and p38 MAP kinases in serum deprivation induced apoptosis in K562 cells and figure out p38 signaling pathway as molecular target for HN delaying apoptosis in K562 cells.
Keywordsapoptosis differentiation humanin K562 cells MAPK
Hashimoto Y, Niikura T, Tajima H, et al.
. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and AΒ. Proc Natl Acad Sci USA
: 6336–6341.CrossRefPubMedGoogle Scholar
Hashimoto Y, Niikura T, Ito Y, et al.
. Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer’s disease-relevant insults. J Neurosci
: 9235–9245.PubMedGoogle Scholar
Hashimoto Y, Ito Y, Niikura T, et al.
. Mechanisms of neuroprotection by a novel rescue factor humanin from Swedish mutant amyloid precursor protein. Biochem Biophys Res Commun
: 460–468.CrossRefPubMedGoogle Scholar
Kariya S, Takahashi N, Ooba N, Kawahara M, Nakayama H, Ueno S. Humanin inhibits cell death of serum-deprived PC12h cells. Neuroreport
: 903–907.CrossRefPubMedGoogle Scholar
Mamiya T, Ukai M. [Gly(14)]-Humanin improved the learning and memory impairment induced by scopolamine in vivo
. Br J Pharmacol
: 1597–1599.CrossRefPubMedGoogle Scholar
Tajima H, Kawasumi M, Chiba T, et al.
. A Humanin derivative, S14G-HN, prevents Amyloid-Β-induced memory impairment in mice. J Neurosci Res
: 714–723.CrossRefPubMedGoogle Scholar
Jung SS, Van Nostrand WE. Humanin rescues human cerebrovascular smooth muscle cells from AΒ-induced toxicity. J Neurochem
: 266–272.CrossRefPubMedGoogle Scholar
Ying G, Iribarren P, Zhou Y, et al.
. Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor. J Immunol
: 7078–7085.PubMedGoogle Scholar
Hashimoto Y, Tsuji O, Niikura T, et al.
. Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death. J Neurochem
: 864–877.CrossRefPubMedGoogle Scholar
Guo B, Zhai DY, Gabezas E, et al.
. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature
: 456–461.CrossRefPubMedGoogle Scholar
Zhai D, Luciano F, Zhu X, Guo B, Satterthwait AC, Reed JC. Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak. J Biol Chem
2005; AOP.Google Scholar
Luciano F, Zhai D, Zhu X, et al.
. Cytoprotective peptide Humanin binds and inhibits pro-apoptotic Bcl-2/Bax-family protein BimEL. J Biol Chem
2005; AOP.Google Scholar
Chang L, Karin M. Mammalian MAP kinase signaling cascades. Nature
: 37–40.CrossRefPubMedGoogle Scholar
Witt O, Sand K, Pekrun A. Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways. Blood
: 2391–2396.PubMedGoogle Scholar
Mayer IA, Verma A, Grumbach IM, et al.
.u The p38 MAPK pathway mediates the growth inhibitory effects of interferon-Ά in BCR-ABL-expressing cells. J Biol Chem
: 28570–28577.CrossRefPubMedGoogle Scholar
Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell
: 239–252.CrossRefPubMedGoogle Scholar
McGee MM, Campiani G, Ramunno A, et al.
. Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells. J Biol Chem
: 18383–18389.CrossRefPubMedGoogle Scholar
Zanjani ED, Almeida-Porada G, Livingston AG, Flake AW, Ogawa M. Human bone marrow CD34
- cells engraft in vivo
and undergo multilineage expression that includes giving rise to CD34
+ cells. Exp Hematol
: 353–360.PubMedGoogle Scholar
Bhatia M, Bonnet D, Murdoch B. A newly discovered class of human hematopoietic cells with SCID-repopulating activity. Nat Med
: 1038–1045.CrossRefPubMedGoogle Scholar
Wang D, Yang L, Li L, et al.
. Identification of differentially expressed genes in Lin-CD34
- and Lin-CD34
+ cells. Chin J Hematol
: 423–425.Google Scholar
Kang CD, Yoo SD, Hwang BW, et al.
. The inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemic K562 cells. Leukemia Res
: 527–534.CrossRefGoogle Scholar
Kim DS, Hwang ES, Lee JE, Kim SY, Park KC. Sphingosine-1-phosphate promotes mouse melanocyte survival via ERK and Akt activation. Cell Signal
: 919–926.CrossRefPubMedGoogle Scholar
Racke FK, Lewandowska K, Goueli S, Goldfarb AN. Sustained activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway is required for megakaryocytic differentiation of K562 cells. J Biol Chem
: 23366–23370.CrossRefPubMedGoogle Scholar
Goldfarb AN, Delehanty LL, Wang D, Racke FK, Hussaini IM. Stromal inhibition of megakaryocytic differentiation correlates with blockade of signaling by protein kinase C-ɛ and ERK/MAPK. J Biol Chem
: 29526–29530.CrossRefPubMedGoogle Scholar
Sponne I, Fifre A, Koziel V, Kriem B, Oster T, Pillot T. Humanin rescues cortical neurons from prion-peptide-induced apoptosis. Mol Cell Neurosci
: 95–102.PubMedGoogle Scholar
Brown JM, Attardi LD. The role of apoptosis in cancer development and treatment response. Nat Rev Cancer
: 231–237.CrossRefPubMedGoogle Scholar
Miyoshi N, Uchida K, Osawa T, Nakamura Y. A link between benzyl isothiocyanate-induced cell cycle arrest and apoptosis: Involvement of mitogen-activated protein kinases in the Bcl-2 phosphorylation. Cancer Res
: 2134–2142.PubMedGoogle Scholar
Lavelle D, DeSimone J, Hankewych M, Kousnetzova T, Chen YH. Decitabine induces cell cycle arrest at the G1 phase via p21 (WAF1) and the G2/M phase via the p38 MAP kinase pathway. Leuk Res
: 999–1007.CrossRefPubMedGoogle Scholar
Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DE, Palerme JS, Newell MK. Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol
: 118–125.CrossRefPubMedGoogle Scholar
Blalock WL, Navolanic PM, Steelman LS, et al.
. Requirement for the PI3K/Akt pathway in MEK1-mediated growth and prevention of apoptosis: Identification of an Achilles heel in leukemia. Leukemia
: 1058–1067.CrossRefPubMedGoogle Scholar
Aisa Y, Miyakawa Y, Nakazato T, et al.
. Fucoidan induces apoptosis of human HS-sultan cells accompanied by activation of caspase-3 and downregulation of ERK pathways. Am J Hematol
: 7–14.CrossRefPubMedGoogle Scholar
Lunghi P, Tabilio A, Dall’Aglio PP, et al.
. Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Leukemia
: 1783–1793.CrossRefPubMedGoogle Scholar
Planey SL, Abrams MT, Robertson NM, Litwack G. Role of apical caspases and glucocorticoid-regulated genes in glucocorticoid-induced apoptosis of pre-B leukemic cells. Cancer Res
: 172–178.PubMedGoogle Scholar
Willaime-Morawek S, Brami-Cherrier K, Mariani J, Caboche J, Brugg B. C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis. Neuroscience
: 387–397.CrossRefPubMedGoogle Scholar
Shelly C, Petruzzelli L, Herrera R. K562 cells resistant to phorbol 12-myristate 13-acetate-induced growth arrest: Dissociation of mitogen-activated protein kinase activation and Egr-1 expression from megakaryocyte differentiation. Cell Growth Differ
: 501–506.PubMedGoogle Scholar
Sorrentino BP. Clinical strategies for expansion of haematopoietic stem cells. Nat Rev Immunol
: 878–888.CrossRefPubMedGoogle Scholar
Domen J, Weissman IL. Hematopoietic stem cells need two signals to prevent apoptosis; Bcl-2 can provide one of these, Kitl/c-Kit signaling the other. J Exp Med
: 1707–1718.CrossRefPubMedGoogle Scholar
© Springer Science + Business Media, Inc. 2005