bcl-2: Role in epithelial differentiation and oncogenesis

Lu, Qilong; Abel, Paul; Foster, Christopher S.; Lalani, El–Nasir

doi:10.1016/s0046-8177(96)90362-7

Cited by 241 publications

(197 citation statements)

References 58 publications

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“…Excess bcl-2 expression may promote the malignant phenotype by suppressing apoptosis (Lu et al, 1996). Mutation of p53 may have the same effect, facilitating unopposed cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

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Cell proliferation, cell loss and expression of bcl-2 and p53 in human pulmonary neoplasms

Kennedy

Lamb²,

King³

et al. 1997

Br J Cancer

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Summary Immunohistochemical staining of bcl-2 and p53 proteins was compared with thymidine labelling index (TLI) and cell loss factor (0) in lung cancer. Neither bcl-2 nor p53 overexpression was associated with high cell loss but strong bcl-2 staining was associated with higher TLI. Concomitant strong p53 and bcl-2 expression, not the usual inverse relationship, plus high cell-loss factor was present in three neuroendocrine carcinomas. Other factors presumably have a role in controlling cell death in these tumours.Keywords: lung carcinoma; neuroendocrine; thymidine labelling index; cell loss factor; bcl-2; p53; apoptosis; immunohistochemistry Apoptosis is a major mechanism of tumour cell loss, itself a major determinant of tumour growth rate, and the protein products of both the p53 and bcl-2 genes have a role in this process. The functions of both these genes and their relationship to other regulatory proteins has been extensively reviewed (Lane, 1993;Piepentol and Vogelstein, 1993;Lu et al, 1996;Yang and Korsmeyer, 1996).In an earlier study (Kerr and Lamb, 1984), we derived data on cell proliferation and cell loss in 17 human lung tumours. Tumour thymidine labelling index (TLI) was measured in vitro and, using recognized methods and formulae (Collins et al, 1956; Steel 1967), a cell loss factor (0) was calculated. Cell loss factor expresses the proportion of cells being lost from a population relative to the number being added to it by mitotic activity. Thus a cell loss factor of 0.90 implies that for every 100 cells being added to a population by mitosis, 90 are lost by whatever means.In this study, we investigate the relationship between the cell proliferation/loss data in these 17 human lung tumours and their expression of the p53 and bcl-2 genes assessed immunohistochemically. MATERIALS AND METHODSThe histological classification of the tumours required revision of the original (Kerr and Lamb, 1984). 'Large-cell carcinoma with stratification' is now classified as poorly differentiated squamous carcinoma. One tumour, thought originally to be a metastatic deposit of large-cell carcinoma, now, with follow-up, fulfils criteria of a primary large-cell neuroendocrine cancer. Thirteen of the cases were typical bronchogenic carcinomas (six squamous, three adenocarcinoma, two small-cell undifferentiated, one largecell neuroendocrine and one large-cell undifferentiated carcinoma). Two were renal cell carcinoma metastases and one a primary clear cell carcinoma.Tumour thymidine labelling index (TLI) was obtained by in vitro incubation of tumour fragments with tritiated thymidine

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“…Excess bcl-2 expression may promote the malignant phenotype by suppressing apoptosis (Lu et al, 1996). Mutation of p53 may have the same effect, facilitating unopposed cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…The functions of both these genes and their relationship to other regulatory proteins has been extensively reviewed (Lane, 1993;Piepentol and Vogelstein, 1993;Lu et al, 1996;Yang and Korsmeyer, 1996).…”

mentioning

confidence: 99%

Cell proliferation, cell loss and expression of bcl-2 and p53 in human pulmonary neoplasms

Kennedy

Lamb²,

King³

et al. 1997

Br J Cancer

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“…This commitment and terminal differentiation also involves induction of the apoptotic machinery for controlled caspase cleavage, enucleation, and internucleosomal DNA cleavage as demonstrated in human keratinocyte differentiation. [43][44][45] Re-localization of A-Raf in our model systems led to activation of MST2 and subsequent activation of caspase 3, cleavage of PARP, and transcriptional activation of PUMA, suggesting a direct involvement of A-Raf in epithelial differentiation.…”

Section: Discussionmentioning

confidence: 76%

“…Commitment and terminal differentiation not only involves regulation of specific genes and epigenetic control, but also induction of the apoptotic machinery for controlled caspase cleavage, enucleation, and internucleosomal DNA cleavage. [43][44][45] We could show recently, that normal epithelia of the head and neck, colon, and liver show decreased levels of A-Raf in comparison to corresponding tumors 16,21,46 and that this feature is regulated via A-Raf splice form selection involving the splice factors hnRNP A2 and H. Although in tumors, splicing is shifted toward enhanced expression of the full-length A-Raf protein that sequesters MST2, normal epithelia, where hnRNP H and hnRNP A2 are low, express the alternatively spliced, truncated isoform A-Raf short , which fails to control MST2. In addition, A-Raf short functions as a dominant-negative mutant due to its ability to bind to activated Ras activation and suppress MAPK activation.…”

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confidence: 99%

Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation

et al. 2016

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A-Raf belongs to the family of oncogenic Raf kinases that are involved in mitogenic signaling by activating the MEK-ERK pathway. Low kinase activity of A-Raf toward MEK suggested that A-Raf might have alternative functions. We recently identified A-Raf as a potent inhibitor of the proapoptotic mammalian sterile 20-like kinase (MST2) tumor suppressor pathway in several cancer entities including head and neck, colon, and breast. Independent of kinase activity, A-Raf binds to MST2 thereby efficiently inhibiting apoptosis. Here, we show that the interaction of A-Raf with the MST2 pathway is regulated by subcellular compartmentalization. Although in proliferating normal cells and tumor cells A-Raf localizes to the mitochondria, differentiated non-carcinogenic cells of head and neck epithelia, which express A-Raf at the plasma membrane. The constitutive or induced re-localization of A-Raf to the plasma membrane compromises its ability to efficiently sequester and inactivate MST2, thus rendering cells susceptible to apoptosis. Physiologically, A-Raf re-localizes to the plasma membrane upon epithelial differentiation in vivo. This re-distribution is regulated by the scaffold protein kinase suppressor of Ras 2 (KSR2). Downregulation of KSR2 during mammary epithelial cell differentiation or siRNA-mediated knockdown re-localizes A-Raf to the plasma membrane causing the release of MST2. By using the MCF7 cell differentiation system, we could demonstrate that overexpression of A-Raf in MCF7 cells, which induces differentiation. Our findings offer a new paradigm to understand how differential localization of Raf complexes affects diverse signaling functions in normal cells and carcinomas. A-Raf is a member of the Raf family of serine-threonine protein kinases, which comprises A-Raf, B-Raf, and Raf-1. Raf kinases are at the apex of the three-tiered Raf/MEK/ extracellular signal-regulated kinase (ERK) (mitogen-activated protein kinase (MAPK)) pathway regulating fundamental cellular functions, including differentiation, transformation, apoptosis, proliferation, and metabolism. 1,2 Activation of Ras GTPases at the cell membrane initiates Raf kinase activation and sequential phosphorylation and activation of the serinethreonine kinases MEK1/2 and ERK1/2. 3,4 In comparison to Raf-1 and B-Raf, A-Raf is only weakly activated by oncogenic H-Ras and Src 5 and is a poor MEK kinase, 5-8 which is due to unique non-conserved amino acid substitutions in the N-region. 9 Only recently, the first somatic oncogenic mutations of A-Raf were identified in lung adenocarcinomas 10 and Langerhans cell histiocytosis. 11,12 We recently showed that A-Raf and Raf-1, independent of their kinase activity, bind the proapoptotic mammalian sterile 20-like kinase (MST2) thereby suppressing MST2 activation and MST2-induced apoptosis. 13-17 MST2 employs several mechanisms to induce apoptosis including the transcriptional induction of PUMA, 14 a BH3 domain protein that causes mitochondrial depolarization and subsequent cell death. 18 Although Raf-1 counteracts MS...

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“…1 In 2005, the American Cancer Society estimates that approximately 232 090 male residents in the US will be diagnosed with prostate cancer and 30 350 will die from the disease. Prostate cancer accounts for approximately 33 and 10% of all new cancer-related cases and deaths among men in the US, respectively. Interestingly, African Americans are approximately 1.6-fold more likely to be diagnosed with prostate cancer when compared to men of European descent.…”

Section: Introductionmentioning

confidence: 99%

Germline BCL-2 sequence variants and inherited predisposition to prostate cancer

Kidd

Coulibaly

Templeton

et al. 2006

Prostate Cancer Prostatic Dis

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Apoptosis is an essential physiological process that regulates cellular proliferation. Here, we explored the effect of DNA sequence variation within the BCL-2 gene on prostate cancer susceptibility in three clinical populations, consisting of 428 African Americans, 214 Jamaicans and 218 European Americans. We observed a 70% reduced risk for prostate cancer among the European Americans who had possessed two copies of a promoter variant À938C/A. Additionally, common BCL-2 haplotypes appeared to influence prostate cancer risk; however, studies in larger data sets are needed to confirm our findings. Our data suggest that inherited BCL-2 variants may be associated with a decrease in prostate cancer susceptibility.

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bcl-2: Role in epithelial differentiation and oncogenesis

Cited by 241 publications

References 58 publications

Cell proliferation, cell loss and expression of bcl-2 and p53 in human pulmonary neoplasms

Cell proliferation, cell loss and expression of bcl-2 and p53 in human pulmonary neoplasms

Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation

Germline BCL-2 sequence variants and inherited predisposition to prostate cancer

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