求两篇近期的Blood文献

呆呆鱼

文献1：( [  K/ [1 w! z8 k2 j7 O8 K) o5 F& m
Blood. 2011 Sep 22. [Epub ahead of print], A) F5 N. s3 b; N1 m8 Y
Inhibition of Rac GTPase signaling and downstream pro-survival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia.
' |$ o: z. E6 u9 NMizukawa B, Wei J, Shrestha M, Wunderlich M, Chou FS, Griesinger A, Harris CE, Kumar AR, Zheng Y, Williams DA, Mulloy JC.5 E6 _; Y, Z# v, q: Y; s9 e
SourceDivision of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States;
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. g$ j+ T( A9 }# u  w0 FAbstract9 r" @. B# G2 a6 I$ U4 h9 }
The Rac family of small Rho GTPases coordinates diverse cellular functions in hematopoietic cells including adhesion, migration, cytoskeleton rearrangements, gene transcription, proliferation, and survival. The integrity of Rac signaling has also been found to critically regulate cellular functions in the initiation and maintenance of hematopoietic malignancies. Using an in vivo gene targeting approach, we demonstrate that Rac2, but not Rac1, is critical to the initiation of acute myeloid leukemia in a retroviral expression model of MLL-AF9 leukemogenesis. However, loss of either Rac1 or Rac2 is sufficient to impair survival and growth of the transformed MLL-AF9 leukemia. Rac2 is known to positively regulate expression of Bcl-2 family proteins towards a pro-survival balance. We demonstrate that disruption of downstream survival signaling through anti-apoptotic Bcl-2 proteins is implicated in mediating the effects of Rac2 deficiency in MLL-AF9 leukemia. Indeed, overexpression of Bcl-xL is able to rescue the effects of Rac2 deficiency and MLL-AF9 cells are exquisitely sensitive to direct inhibition of Bcl-2 family proteins by the BH3-mimetic, ABT-737. Furthermore, concurrent exposure to NSC23766, a small-molecule inhibitor of Rac activation, increases the apoptotic effect of ABT-737, indicating the Rac/Bcl-2 survival pathway may be targeted synergistically.
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! a# _; Y- b3 \; r" `# j; k: T% }PMID: 21940819 [PubMed - as supplied by publisher]
( w- v8 y% _% ~9 Z链接： http://www.ncbi.nlm.nih.gov/pubmed/219408194 c5 J7 n0 |+ B

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% d7 _  C8 R4 ]9 R) n- ~Blood. 2011 Jun 9;117(23):6214-26. Epub 2011 Apr 7.
: z+ z( X1 Y0 }1 k5 x$ ZThe small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity.
$ g  Q$ z) W! ^1 \0 xVelaithan R, Kang J, Hirpara JL, Loh T, Goh BC, Le Bras M, Brenner C, Clement MV, Pervaiz S.& G# w6 u# H% E: Z, B
SourceDepartment of Physiology, Yong Loo Lin School of Medicine, Singapore.
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The small GTPase Rac1 is involved in the activation of the reduced NAD phosphate oxidase complex resulting in superoxide production. We recently showed that Bcl-2 overexpression inhibited apoptosis in leukemia cells by creating a pro-oxidant intracellular milieu, and that inhibiting intracellular superoxide production sensitized Bcl-2-overexpressing cells to apoptotic stimuli. We report here that silencing and functional inhibition of Rac1 block Bcl-2-mediated increase in intracellular superoxide levels in tumor cells. Using confocal, electron microscopy and coimmunoprecipitation, as well as glutathione S-transferase-fusion proteins, we provide evidence for a colocalization and physical interaction between the 2 proteins. This interaction is blocked in vitro and in vivo by the BH3 mimetics as well as by synthetic Bcl-2 BH3 domain peptides. That this interaction is functionally relevant is supported by the ability of the Bcl-2 BH3 peptide as well as the silencing and functional inhibition of Rac1 to inhibit intracellular superoxide production as well as overcome Bcl-2-mediated drug resistance in human leukemia cells and cervical cancer cells. Notably, the interaction was observed in primary cells derived from patients with B-cell lymphoma overexpressing Bcl-2 but not in noncancerous tissue. These data provide a novel facet in the biology of Bcl-2 with potential implications for targeted anticancer drug design.
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PMID: 21474673 [PubMed - indexed for MEDLINE]
0 [+ S( E) U1 X6 ^链接： http://www.ncbi.nlm.nih.gov/pubmed/21474673

呆呆鱼

最近有急用，谢谢了

woshimiyun

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