Flowchart: Preparation: Bcl2
 

  A

 
 
 
 

 D-G

 

 BC

 
        

 

Text Box: Jak3Text Box: AiolosText Box: Bax  

Biocarta                                                     

Cancer

AD :

Text Box: Bcl2B-cell lymphoma

COPD

Hematologic disorder

Leukemia

Lung

Non-Hodgkin Lymphomas

Oral cancer

Text Box: P53Text Box: ApafStem cell

 

Text Box: C-Myc
 


       

Stress Induction of HSP regulatiosn

P53 signaling pathway

Ras Signaling Pathway

Akt Signaling Pathway                  

Apoptosis signaling in response to DNA damage

5/12/2007/-13                                

Exp Hematol. 2007 Nov 17 [Epub ahead of print]Click here to read Links

Bcl2 enhances induced hematopoietic differentiation of murine embryonic stem cells.

Wang YY, Deng X, Xu L, Gao F, Flagg T, May WS.

University of Florida Shands Cancer Center and Department of Medicine, University of Florida, Gainesville, Fla., USA.

Bcl2 is a potent antiapoptotic gene that can increase resistance of adult bone marrow hematopoietic progenitor cells to lethal irradiation, and thereby preserve their ability to differentiate. However, the effect of Bcl2 on murine embryonic stem (ES) cells induced to undergo hematopoietic differentiation in the absence of a toxic stress is not known. To test this, murine CCE-ES cells that can be induced to undergo hematopoietic differentiation in a two-step process that results in upregulation of Bcl2 were used. Upregulation of Bcl2 precedes formation of hematopoietic embryoid bodies (EB) and their further differentiation into hematopoietic colony-forming units, when plated as single cells in methylcellulose. ES cells stably expressing a Bcl2 siRNA plasmid to "knock-down" endogenous expression or cells expressing wild-type (WT) Bcl2 or phosphomimetic Bcl2 mutants were examined. ES cells expressing the Bcl2 siRNA or those expressing a dominant-negative, nonphosphorylatable Bcl2 display a strikingly reduced capacity to form hematopoietic EBs and colony-forming units compared to cells expressing WT or phosphomimetic Bcl2 that demonstrate an increased capacity. Bcl2's effect on induced-hematopoietic differentiation of ES cells does not result from either decreased apoptosis or a reduced number of cells. Rather, Bcl2-enhances hematopoietic differentiation of ES cells by upregulating p27, which results in retardation of the cell cycle at G(1)/G(0). Thus siRNA silencing of p27 reverts Bcl2's enhancement phenotype in a manner similar to that of Bcl2 "silencing" or expression of a nonphosphorylable Bcl2. In addition to Bcl2's well-described antiapoptotic and cell-cycle retardant effect on somatic cells, Bcl2 may also function to enhance induced hematopoietic cell differentiation of murine ES cells. These findings may have potential relevance for expanding hematopoietic stem/progenitor cell numbers from an ES cell source for stem cell transplantation applications.

PMID: 18023519 [PubMed - as supplied by publisher]

 

J Biol Chem. 2006 Mar 22; [Epub ahead of print]

Related Articles, Links

Click here to read 
Bcl2 suppresses DNA repair by enhancing c-Myc transcriptional activity.

Jin Z, May WS, Gao F, Flagg T, Deng X.

Department of Medicine, University of Florida Shands Cancer Center, Gainesville, FL 32610-0232.

Bcl2 and c-Myc are two major oncogenic proteins that can functionally promote DNA damage, genetic instability and tumorigenesis. However, the mechanism(s) remains unclear. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the most potent carcinogen contained in cigarette smoke that induces cellular DNA damage. Here we found that Bcl2 potently suppresses the repair of NNK-induced abasic sites of DNA lesions in association with increased c-Myc transcriptional activity. Bcl2's BH4 domain (aa 6-31) was found to bind directly to c-Myc's MBII domain (aa 106-143) and this interaction is required for Bcl2 to enhance c-Myc transcriptional activity and inhibit DNA repair. In addition to mitochondria, Bcl2 is also expressed in the nucleus where it co-localizes with c-Myc. Expression of nuclear-targeted Bcl2 enhances c-Myc transcriptional activity with suppression of DNA repair but fails to prolong cell survival. Depletion of c-Myc expression from cells overexpressing Bcl2 significantly accelerates the repair of NNK-induced DNA damage, indicating that c-Myc may be essential for Bcl2's effect on DNA repair. It is known that APE1 plays a crucial role in the repair of abasic sites of DNA lesions. Since overexpression of Bcl2 results in up-regulation of c-Myc and down-regulation of APE1, this suggests that APE1 may function as the downstream target of Bcl2/c-Myc in the DNA repair machinery. Thus, Bcl2, in addition to its survival function, may also suppress DNA repair in a novel mechanism involving c-Myc and APE1, which may lead to an accumulation of DNA damage in living cells, genetic instability and tumorigenesis.

PMID: 16554306 [PubMed - as supplied by publisher]

 

: Am J Dermatopathol. 1996 Jun;18(3):273-7.Click here to read  Links

Expression of bcl-2 and p53 in Merkel cell carcinoma. An immunohistochemical study.

P     Kennedy MM, Blessing K, King G, Kerr KM.

Department of Pathology, Aberdeen University, Foresterhill, Scotland.

Bcl-2 is a protooncogene thought to play a role in oncogenesis by inhibiting programmed cell death. It may interact with p53, a tumor-suppressor gene which induces apoptosis in certain circumstances. We have studied these gene products by immunohistochemistry in 15 cases of Merkel cell carcinoma, a tumor characterised by prominent apoptosis. Five cases showed moderate/strong staining for p53, with moderate/strong bcl-2 staining in 10 patients. In seven cases abundance of p53 and bcl-2 expression was mutually exclusive. Two patients died within 1 year of diagnosis and six had nodal recurrences. Gene expression and survival appear unrelated. The role of Bcl-2 and p53 in tumorigenesis is complicated and may be inter-related with other genes known to be involved in programmed cell death.

PMID: 8806961 [PubMed - indexed for MEDLINE]

Diabetes Metab Res Rev. 2007 Feb 22; [Epub ahead of print]Click here to read  Links

Leptin decreases apoptosis and alters BCL-2 : Bax ratio in clonal rodent pancreatic beta-cells.

P     Brown JE, Dunmore SJ.

Diabetes and Metabolic Disorders Research Group, RIHS, University of Wolverhampton, Wulfruna St, Wolverhampton, WV1 1SB, UK.

AIMS/HYPOTHESIS: The adipocyte derived peptide hormone leptin is known to regulate apoptosis and cell viability in several cells and tissues, as well as having several pancreatic islet beta-cell specific effects such as inhibition of glucose-stimulated insulin secretion. This study investigated the effects of leptin upon apoptosis induced by serum depletion and on expression of the apoptotic regulators B-cell leukaemia 2 gene product (BCL-2) and BCL2-associated X protein (Bax) in the glucose-responsive BRIN-BD11 beta-cell line. METHODS: BRIN-BD11 cells were cultured in RPMI 1640 and subsequently serum depleted +/- leptin (10 and 50 ng/mL) for 24 h. Cell viability and apoptosis were measured using a modified MTS assay and TUNEL/YO-PRO-1 assays, respectively. BCL-2 and Bax expression were measured by real-time PCR and Western blotting. RESULTS: Leptin caused a reduction in serum-depleted apoptosis, although it failed to have any effect on the overall cell viability, causing a 68% shift from apoptosis to necrosis. Leptin significantly increased the level of BCL-2 mRNA expression (150% compared to serum depletion alone), without altering Bax mRNA expression. At the protein level, leptin increased BCL-2 and decreased Bax, altering the BCL-2 : Bax ratio. CONCLUSIONS: We conclude that leptin reduces apoptosis in beta-cells at physiological concentrations, possibly via its ability to up-regulate BCL-2 and Bax expression. Copyright (c) 2007 John Wiley & Sons, Ltd.

PMID: 17318810 [PubMed - as supplied by publisher

Drug Resist Updat. 2007 Feb 12; [Epub ahead of print] Links

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy.

P     Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A, Eshraghi M, Manda KD, Wiechec E, Los M.

Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.

The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16(Ink4a), p15(Ink4b), p18(Ink4c), p19(Ink4d)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G(1)-S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.

PMID: 17303468 [PubMed - as supplied by publisher