The antiapoptotic Bcl-2 protein is overexpressed in a variety of cancers, particularly leukemias. In some cell types this is the result of enhanced stability of bcl-2 mRNA, which is controlled by elements in its 3-untranslated region. Nucleolin is one of the proteins that binds to bcl-2 mRNA, thereby increasing its halflife. Here, we examined the site on the bcl-2 3-untranslated region that is bound by nucleolin as well as the protein binding domains important for bcl-2 mRNA recognition. RNase footprinting and RNA fragment binding assays demonstrated that nucleolin binds to a 40-nucleotide region at the 5 end of the 136-nucleotide bcl-2 AU-rich element (ARE bcl-2 ). The first two RNA binding domains of nucleolin were sufficient for high affinity binding to ARE bcl-2 . In RNA decay assays, ARE bcl-2 transcripts were protected from exosomal decay by the addition of nucleolin. AUF1 has been shown to recruit the exosome to mRNAs. When MV-4-11 cell extracts were immunodepleted of AUF1, the rate of decay of ARE bcl-2 transcripts was reduced, indicating that nucleolin and AUF1 have opposing roles in bcl-2 mRNA turnover. When the function of nucleolin in MV-4-11 cells was impaired by treatment with the nucleolin-targeting aptamer AS1411, association of AUF1 with bcl-2 mRNA was increased. This suggests that the degradation of bcl-2 mRNA induced by AS1411 results from both interference with nucleolin protection of bcl-2 mRNA and recruitment of the exosome by AUF1. Based on our findings, we propose a model that illustrates the opposing roles of nucleolin and AUF1 in regulating bcl-2 mRNA stability.Bcl-2, the prototype for its family, is an antiapoptotic protein. Its overexpression has been implicated in multiple cancers and associated with resistance to chemotherapy, making it an important prognostic factor, particularly in hematological malignancies. The Bcl-2 protein is often highly expressed in chronic lymphocytic leukemia (CLL), 5 even though there is no evidence of gene rearrangements that are known to up-regulate bcl-2 transcription. Recently, Otake et al.(1) reported that Bcl-2 overexpression in CLL is related to bcl-2 mRNA stabilization.It is becoming increasingly clear that mRNA stability is an important control point in the regulation of gene expression. In mammalian cells, regulation of mRNA turnover can dramatically alter the abundance of a particular mRNA without changes in transcription. One of the best characterized regulatory elements present in the 3Ј-untranslated region (3Ј-UTR) of mRNAs is the AU-rich element (ARE) (for a review, see Ref.2). These elements are usually composed of AUUUA sequences embedded in a U-rich stretch, and they act as potent mRNA-destabilizing sequences, targeting mRNAs for rapid decay. The bcl-2 mRNA contains an ARE in the 3Ј-UTR that plays a role in regulating its stability (3, 4). The ARE bcl-2 is a sequence of 136 nucleotides (nucleotides 921-1057) just downstream from the stop codon, containing two AUUUA pentamers and a UUAUUUAUU nonamer, which has also been shown to destabili...
Overexpression of the proto-oncogene bcl-2 promotes abnormal cell survival by inhibiting apoptosis. Expression of bcl-2 is determined, in part, by regulatory mechanisms that control the stability of bcl-2 mRNA. Elements in the 3′-untranslated region of bcl-2 mRNA have been shown to play a role in regulating the stability of the message. Previously, it was found that the RNA binding proteins nucleolin and Ebp1 have a role in stabilizing bcl-2 mRNA in HL60 cells. Here, we have identified HuR as a component of bcl-2 messenger ribonucleoprotein (mRNP) complexes.
The current study was aimed to study the anticancer potential of Ipomoea carnea towards Ehrlich ascites carcinoma (EAC) bearing mice. Ethanolic extract of Ipomoea carnea (leaves) was assessed for in vivo anticancer potential. The albino mice of either sex separated into five groups of six animals each. Group I served as normal control, group II served as tumor control, group III and IV animals received different concentrations of plant extract of tumor inoculation (150 mg/kg.bw, 300mg/kg.bw) after 24 h for 14 days. Standard drug 5 fluorouracil (20mg/kg.bw) was given to group V animals for 14 days. Before the treatment, all the group's mice were inoculated with EAC (1×10 6 cells/mice) except the group I animals. After an experimental time, the tumor volume, tumor cell count, viable and non-viable cell count were analyzed using the ascites fluid. The animals were slaughtered by cervical decapitation, the blood was stored and used to hematological and biochemical studies. The liver homogenate was used for antioxidant and glycoprotein profiles. The ethanolic extract of Ipomoea carnea (EEIC) administration at different dose increased the life span and reduced the viable cell counts and ascites fluid volume. Administration of plant extract restored the altered levels of antioxidant parameters like SOD, reduced glutathione, LPO and catalase activity. It also decreased the nucleic acid content and glycoprotein level of a tumour bearing animals. Thus the study revealed that Ipomoea carnea has significant anticancer activity against EAC bearing mice.
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