Apoptosis

Johnstone, Ricky W.; Ruefli, Astrid A.; Lowe, Scott W.

doi:10.1016/s0092-8674(02)00625-6

Cited by 1,986 publications

(641 citation statements)

References 82 publications

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“…Cancer cells die as a consequence of apoptosis owing to prolonged arrest in either G1/S or G2/M phases of cell cycle or owing to their inability to replicate (Johnstone et al, 2002). We found that diminished viability of cells upon Mid-and 13L-shRNA expression (Figure 5a, c-g) was not due to defective cell proliferation (Figure 5b) or perturbed cell cycle progression (not shown), but was a direct consequence of spontaneous apoptosis.…”

Section: Discussionmentioning

confidence: 74%

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

et al. 2006

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The IG20 gene is overexpressed in human tumors and cancer cell lines, and encodes at least four splice variants (SVs) namely, IG20pa, MADD, IG20-SV2 and DENN-SV. Earlier, gain-of-function studies showed that IG20-SVs can exhibit diverse functions and play a critical role in cell proliferation and apoptosis. Expression of exogenous IG20pa or DENN-SV rendered cells either susceptible or resistant to induced apoptosis, respectively, whereas MADD and IG20-SV2 had no apparent effect. In order to understand the contrasting effects of the IG20-SVs in a physiologically more relevant system, we expressed exonspecific small hairpin RNAs (shRNAs) to selectively knockdown specific IG20-SVs. Consistent with an earlier study, knockdown of all IG20-SVs resulted in spontaneous apoptosis of HeLa and PA-1 cells. In addition, we unambiguously demonstrated that knockdown of MADD can render cells susceptible to spontaneous apoptosis but had no discernible effect on cell proliferation, colony size or cell cycle progression. Moreover, expression of MADD alone, and not DENN-SV, in the absence of endogenous IG20-SVs was sufficient to prevent spontaneous apoptosis. Our results show the utility of shRNAs for selective knockdown of particular IG20-SVs and their potential therapeutic value in cancer. Further, they demonstrate that MADD alone is sufficient and necessary for cancer cell survival.

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Section: Discussionmentioning

confidence: 74%

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

et al. 2006

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“…As impaired apoptosis plays a central role in oncogenesis, the search is accelerating for novel agents that engage the cell death machinery (Nicholson, 2000;Johnstone et al, 2002). Impaired apoptosis is also a significant impediment to cytotoxic therapy.…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Mitochondria and cancer: is there a morphological connection?

2006

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Mitochondria are key players in several cellular functions including growth, division, energy metabolism, and apoptosis. The mitochondrial network undergoes constant remodelling and these morphological changes are of direct relevance for the role of this organelle in cell physiology. Mitochondrial dysfunction contributes to a number of human disorders and may aid cancer progression. Here, we summarize the recent contributions made in the field of mitochondrial dynamics and discuss their impact on our understanding of cell function and tumorigenesis.

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“…Disruption of apoptosis clearly contributes to the pathogenesis of cancer, and is a contributing factor in chemotherapeutic resistance observed in many human tumor cells (Thompson, 1995). Indeed, suppression of apoptosis is a consistent characteristic of tumors and malignantly transformed cells (Johnstone et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

Huang

et al. 2006

Oncogene

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Ultraviolet A (UVA, 315-400 nm), constituting about 95% of ultraviolet irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. It has proven difficult to show direct actions of UVA as a carcinogen in human cells. Here, we demonstrate that chronic UVA exposures at environmentally relevant doses in vitro can induce malignant transformation of human keratinocytes associated with acquired apoptotic resistance. As evidence of carcinogenic transformation, UVAlong-treated (24 J/cm 2 once/week for 18 weeks) HaCaT (ULTH) cells showed increased secretion of matrix metalloproteinase (MMP-9), overexpression of keratin 13, altered morphology and anchorage-independent growth. Malignant transformation was established by the production of aggressive squamous cell carcinomas after inoculation of ULTH cells into nude mice (NC r -nu). ULTH cells were resistant to apoptosis induced not only by UVA but also by UVB and arsenite, two other human skin carcinogens. ULTH cells also became resistant to apoptosis induced by etoposide, staurosporine and doxorubicin hydrochloride. Elevated phosphorylation of protein kinase B (PKB, also called AKT) and reduced expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were detected in ULTH cells. The resistance of ULTH cells to UVA-induced apoptosis was reversed by either inhibition of phosphatidylinositol 3-kinase (PI-3K) or adenovirus expression of PTEN or dominant negative AKT. These data indicate that UVA has carcinogenic potential in human keratinocytes and that the increased AKT signaling and decreased PTEN expression may contribute to this malignant transformation. Further comparisons between the transformed ULTH and control cells should lead to a better understanding of the mechanism of UVA carcinogenesis and may help identify biomarkers for UVA-induced skin malignancies.

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Apoptosis

Cited by 1,986 publications

References 82 publications

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

Mitochondria and cancer: is there a morphological connection?

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

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