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8-Br-cAMP可上调人视网膜母细胞瘤HXO-Rb44细胞抑癌基因的表达

http://www.cnophol.com 2009-7-13 10:38:16 中华眼科在线

  RESULTS

  Our results showed that t he dot blot signals of p16,p21wafl,wp 53 and Rb antioncogenes in EG were all h igher than those in CG,P<0.05~0.01,the signals of mp53 in EG was lower than t hat in CG(see Tab.1).

  The immunost aining revealed that the dot blot immuno reactivity of P16,P21wafl and PRb protein expres-sion in human HXO-Rb44 ce lls were all stronger in EG than those i n CG,P<0.05,but the PCNA-IR,cdk2-IR a nd cdk4-IR were weaker in EG than those in CG,P<0.01.

  DISCUSSION

  In the present ex periment the results showed that 8-Br-cA MP could decrease the cell prolifera tion with PCNA staining,indicating that 8-Br-cAMP could inhibit the growth of hu man HXO-Rb44 cells.It has been reported that P16INK4 coded by the multiple tu mor suppressor (MTS) was an inhibitor of the cell cycle by the function of inhib ition binding cdk4 with cyclinD1 to bl ock the cell proliferation[5].The pre sent results showed that 8-Br-cAMP could up-regulate expression of p16INK4 mRNA and P16 gene product and down-regulat e the expression of cdk4,suggesting that 8 -Br-cAMP may inhibit the HOX-Rb44 cell g rowth through inhibition of cell cycle b y P16 coded MTS gene.

  The inhibition of the cell cycle by the wild type of P 53(wP53) was indirect.The P53 pr otein acting as a transactivator coded b y wp53 may activate the gene expression of p21wafl.The P21wafl protein can inhibit the binding of cdk2 with cyclin E to block the cell growth and prevent the cell cycle from G1 into S phase[ 6,7].Furthermore the results showed tha t 8-Br-cAMP could up-regulate wp53 mRNA and p21 wafl and down-regulate the mut ant type p53(mp53) mRNA and cdk2,sugg esting that 8-Br-cAMP may block the cell cycle to inhibit the HXO-Rb44 cell grow th through activating P21wafl mediate d by wP53.

  Antioncogene Rb plays a re gulatory role through phosphorylation an d dephosphorylation of cdks.The phosphor y lated PRb losses the inhibitory effect o n G1 phase,while the dephosphorylatedd PRb possesses the inhibitory function.Th e P16INK4 or P21wafl can combine w ith cdks,such as cdk2,cdk4 in competit ion with cyclins,hence cdks cannot be ac tivated by cyclins and Rb cannot be phos phorylated.The cell cycle check point is blocked by phosphorylated PRb[8].The carcinogenesis of human retinoblastoma may be caused by defect of Rb gene.In th e present experiment the 8-Br-cAMP could up-regulate the expression of Rb mRNA a nd PRb-IR.It suggests that 8-Br-cAMP may inhibit HXO-Rb44 cell growth through th e activation of Rb antioncogene.

  The sup pressor oncogene,including p53,p16 and Rb often were inactivated by mutation o r delection in the malignent tumor,espec ially p53 gene.In this study the wp53 mRNA and mp53 mRNA expression were demo nstrated by wp53 cDNA probe and mp53 c DNA probe respectively.Since the wP53 h alf life is very short and the P53-IR belongs predominantly to mP53 by imm unohistochemistry[9],so that P53-I R were not examined in our experiment.

  Lukas and Shapiro[10,11] reported tha t there was a negative correlation betwe en the expression of PRb and P16.A lo w level of PRb could stimulate the trans cription of P16 and there was a feedback regula tory circuit among cyclin D1,cdk4,P1 6 and PRb[12].At the level of mRNA e xpression the intensity of the signals w as similar to that of protein expression and there was a coincidence in intensit y between the gene expression and protei n product detected by the stringent in s itu RNA blot and protein blot in this ex periment.The results suggested that 8-Br -cAMP inhibits HXO-Rb44 cell growth via up-regulation of the wp53,p16 and Rb.

  REFERENCES

  1,Zhang P.Therapeutic advance ment of retinoblastoma.Clin Ophthal Res, 1997,15∶288

  2,Cho-Chung YS.Site-sel ective 8-chloro-cyclic adenosine 3’5’m on ophosphate as biologic modulator of canc er:resolution of normal control mechanis m.J Natl Cancer Inst,1989,8∶982

  3,Katsaros D,Tortora G,Tafliagerri P,e t al.Site-selective cyclic AMP analogs p rovide a new approach in the control of cancer cell growth.FEBS Lett,1987,223∶97

  4,Wu Jinglan,Ding Yi.Pr actica l Protocals of Non-radioactive Biotech.Z hengzhou:Henan Medical University Press, 1997.56-63,88-93

  5,Kamb A,Grui s NA,Weaver-Feldhaus J,et al.A cell cycl e regulator potenliatly involved in gene sis of many tumor types.Science,1994,264 ∶436

  6,Shimamura A,Fishe r DE.p 53 in life and death.Clin Cancer Res,19 96,2∶435

  7,Harper JW,Ada ml GR, Wei N,et al.The P21 cdk-interacting p rotein cipI is a potent inhibitor of G 1 cyclin-dependent kinases.Cell,1993,75∶ 805

  8,Xu B.The role of R b in c ell cycle regulation.Foreign Medical Sci ences(Molecular Biology),1995,17∶211

  9,Li JL,Yang GH,Li GD.The poi nt mut ation of p53 gene in the malignant fibr oma detected silver straining PCR-SSCP t echnique.Chin J Oncol,1996,18∶13

  10,Lukas J,Parry D,Agaard L,et al.Ret inoblastoma-protein dependent cell-cycle inhibition by the tumor supressor P16. L etters to Nature,1995,375∶503

  11,Shapiro GI,Edwards CD,Kobzik L,et al. Reciprocal Rb inactivation and P16INK4 expression in primary lung cancers and cell lines.Cancer Res,1995,55∶505

  12,Serrano M,Hannon GJ,Beach D.A ne w regulatory motif in cell cycle control causing specific inhibition of cyclin D /CDK4.Nature,1993,366∶704

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