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Bcl-2 Proteins and Regulators

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Bcl-2 Proteins and Regulators

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Bcl-2 Proteins and Regulators Background

Bcl-2 gene is an important member of the Bcl-2 gene family. This gene was first found in mouse B-cell lymphoma, hence the name Bcl-2 (B-cell lymphoma/leukemia-2). Gene research has focused on their regulation of the entire apoptotic process, but in recent years it has been discovered that the Bcl-2 gene and its protein have a wider role, and their overexpression and phosphorylation are also involved in the regulation of cell proliferation , And plays an important role in tumor formation and tumor multidrug resistance.

Biological characteristics of Bcl-2 gene

The Bcl-2 gene family is one of the most important gene families that regulate apoptosis. The members of the Bcl-2 gene family that have been discovered include Bcl-2, bcl-xl, bcl-w that inhibit apoptosis. A1, Mcl-1, Bfl -1, etc; Bcl-xs, Hrk, etc. Although members of this family have different expressions in different tissues, they are There are common structural differences: one is a hydrophobic transmembrane domain (TM) at the carbon end, which determines the subcellular localization of the protein, and the other is that they contain four conserved BH domains (BH1-BH4), of which BH1 and BH2 It is shared by them and participates in the dimerization of Bcl-2 family members; BH3 domain is indispensable for the pro-apoptotic activity of Bcl-2 family members; experiments have confirmed that Bcl-2 mutants lacking BH4 or containing mutant BH4 cannot Prevents apoptosis, so the BH4 domain is considered to be necessary for the anti-apoptotic activity of members of the Bcl-2 family. The Bcl-2 gene is an important member of the Bcl-2 gene family, and this gene was first found in mouse B-cell lymphoma It was found that it is called Bcl-2. Bcl-2 protein is generally located in the mitochondrial membrane, endoplasmic reticulum membrane, and nuclear membrane, Ion channels, and having a dual role docking protein, Bcl-2 protein expression in primary and specifict chromosome translocation related.

Bcl-2 gene action mechanism. Figure 1. Bcl-2 gene action mechanism.

Bcl-2 and apoptosis

Bcl-2 gene is an important apoptosis-inhibiting gene. Transgenic animals and gene transfection experiments have shown that Bcl-2 gene and its expressed protein can inhibit apoptosis of a variety of tissue cells, prolong cell life, and it can inhibit multiple factors. Therefore, it is also called "survival gene". He mainly plays its role in regulating apoptosis by dimerizing itself or forming a heterodimer with proteins such as Bax. The binding of Bcl-2 protein and membrane is important for its function. Importantly, experiments have shown that Bcl-2 proteins that have lost membrane localization ability have significantly reduced anti-apoptotic capacity, and Bcl-2 proteins with different subcellular localizations may participate in different apoptotic pathways in different types of cells. 2 Ca2+ plays a very important role in inhibiting cell apoptosis. The digestion of DNA during apoptosis requires the participation of related Ca2+ -dependent endonuclease, and the Bcl-2 protein on the endoplasmic reticulum membrane can prevent the release of Ca2+ in the endoplasmic reticulum and reduce the Ca2+ -dependent endonuclease Activity, thereby preventing apoptosis. Bcl-2 protein may also act on signal molecules on the mitochondria and nuclear pore complex to control cell signal transduction Guide, prolong cell growth Additionally, Bcl-2 protein may exert its antioxidant action or inhibiting free radical oxidation produced by regulating the transcription factor NF-kappaB, inhibition of apoptosis.

Bcl-2 and Cellular apoptosis pathway. Mitochondrial apoptotic pathway Figure 2. Bcl-2 and Cellular apoptosis pathway. Mitochondrial apoptotic pathway(LI Xiao-xian, et al. Acta Pharmaceutica Sinica, 2018)

The role of Bcl-2 in cell proliferation

Although Bcl-2 protein and its similar proteins play an important role in the regulation of apoptosis, their overexpression in cell lines and transgenic animals revealed that they are also involved in the regulation of cell proliferation. Functional analysis of Bcl-2 mutation It has also been shown that the cell cycle regulation function of Bcl-2 family members is to a certain extent independent of its apoptosis regulation function.

Bcl-2 gene and tumor

The maintenance of the number of cells in various tissues in the human body is achieved by the balance between cell proliferation and death. If the rate of cell proliferation accelerates and the rate of death slows down, both can cause abnormal cell growth in the body and lead to tumorigenesis. It has been proven Inhibition of programmed cell death is the most critical step in the process of tumor formation. As an important apoptosis-inhibiting gene, The Bcl-2 gene disrupts the homeostasis mechanism of cells, preventing damaged or mutated cells from being cleared in time and developing into tumors under the synergistic effect of proliferative genes and growth inhibitory genes. In mouse bone marrow cells, retrovirus mediated Bcl-2 protein overexpression, analysis showed that only overexpression of Bcl-2 could not lead to Tumor formation. In vitro experiments show that when the effect of IL-3 is removed, IL-3 dependent lymphocytes and bone marrow cells gradually turn to apoptosis; and after Bcl-2 cDNA is introduced into cells, this apoptosis phenomenon It is inhibited. It can be seen that Bcl-2 prolongs cell life by inhibiting apoptosis, cell accumulation, and initiates action in tumorigenesis. Recent research shows that Bcl-2 can interact with blood vessels Endothelial growth factors and other interactions affect tumor angiogenesis and promote tumor formation and development. Bcl-2 was originally proposed as an oncogene in lymphoma, and subsequent studies have shown that many human tumors have high levels of Bcl-2. Expression, such as liver cancer, prostate cancer, etc., is currently considered that the high expression of Bcl-2 is not a characteristic of a tumor, but reflects a proliferative state of tumor cells.

 Overview of signal transduction pathways involved in apoptosis. Figure 3. Overview of signal transduction pathways involved in apoptosis.(From wikipedia)

References:

  1. Borner C. The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol. 2003; 39: 615-647.
  2. Coultas L, Strasser A. The role of the Bcl-2 protein family in cancer. Semin Cancer Biol. 2003; 13: 115-123.
  3. Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G. Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene. 1998; 16: 2265-2282.
  4. Scorrano L, Korsmeyer SJ. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun. 2003; 304: 437-444.
  5. Kirkin V, Joos S, Zörnig M. The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta. 2004; 1644: 229-249.
  6. Matolcsy A, Warnke RA, Knowles DM. Somatic mutations of the translocated bcl-2 gene are associated with morphologic transformation of follicular lymphoma to diffuse large-cell lymphoma. Ann Oncol. 1997;8 Suppl 2:119-122.
  7. Mazurek A, Pierzynski P, Niklinska W, Chyczewski L, Laudanski T. Angiogenesis and Bcl-2 protein expression in patients with endometrial carcinoma. Neoplasma. 2002; 49 :149-154.
  8. Dias S, Shmelkov SV, Lam G, Rafii S. VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood. 2002; 99:2532-2540.

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