Expression profiles of p63, p53, survivin, and hTERT in skin tumors

Park, Hye-Rim; Min, Soo Kee; Cho, Hyun Deuk; Kim, Kwang Ho; Shin, Hyung Sik; Park, Young Euy

doi:10.1111/j.0303-6987.2004.00228.x

Cited by 66 publications

(96 citation statements)

References 35 publications

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“…The increased apoptosis in the colonies of untreated hTERT þ cells compared to hTERTÀ cells was unexpected but is in keeping with the increased apoptosis of transformed MIN6 pancreatic cells when grown as three-dimensional clusters rather than monolayers (Luther et al, 2005) and with the apoptosis seen in malignant and even pre-malignant tumours (e.g. Bowen's disease, which is hTERT positive (Park et al, 2004)) compared to their benign counterparts. The lack of increased apoptosis and reduced loss of cell viability in hTERT þ cells after metal treatment emphasizes the link between cell death and telomerase which has been noted in tumours during the development of drug resistance to chemotherapy including metal (cisplatin) (Mese et al, 2001).…”

Section: Metal-induced Genomic Instabilitymentioning

confidence: 54%

Effects of hTERT on metal ion-induced genomic instability

et al. 2006

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There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longerterm genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERTÀ cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased b-galactosidase staining and apoptosis. This instability was not present in telomerasepositive hTERT þ cells. In contrast, in hTERT þ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERTÀ cells. The growth and survival of both metal-exposed hTERT þ and hTERTÀ cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

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Section: Metal-induced Genomic Instabilitymentioning

confidence: 54%

Effects of hTERT on metal ion-induced genomic instability

et al. 2006

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“…Lack of caspase 3 resulted in increased proliferation and decreased differentiation of embryonic keratinocytes 36. However, the possible involvement of this pathway in CSCC remains to be clarified, although increased expression of survivin, an apoptosis inhibitor targeting caspase 3 and caspase 7, was observed in CSCC tumors 37, 38, 39.…”

Section: Notch Signaling In Cutaneous Squamous Cell Carcinoma (Cscc)mentioning

confidence: 99%

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

et al. 2016

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The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro‐oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

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“…In our system using human papillomavirus (HPV)16 E6/7 immortalized keratinocytes (KC), we found that the immortalized cells mimicked AK in that, while p53 and Rb pathways were blocked and hTERT was constitutively expressed (Park et al, 2004), the cells were exquisitely sensitive to UVB apoptosis compared to primary KC from which they were derived (Simbulan-Rosenthal et al, 2002). We further found that this sensitivity was due in part to downregulation of Bcl2, which resulted in the activation of caspases-9 and -3 at much lower doses of UVB (Simbulan-Rosenthal et al, 2002).…”

Section: Introductionmentioning

confidence: 95%

“…In contrast, the rates of AK progression to SCC are much lower, with rate estimates of 0.2% (Marks et al, 1986), 0.1% (Marks et al, 1988), and 0-1.1% per year (Frost et al, 2000). While the exact details are yet to be elucidated, an insight into the molecular mechanisms of AK regression can be gleaned from studies in which expression of immortalizing and survival proteins were examined in normal skin, porokeratosis, AK, SCC in situ, and invasive SCC (Park et al, 2004). Interestingly, the majority of premalignant lesions, like the malignant lesions, demonstrated stable expression of hTERT.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the majority of premalignant lesions, like the malignant lesions, demonstrated stable expression of hTERT. However, unlike their premalignant precursors, the majority of SCC in situ and invasive SCC were found to be blocked in apoptotic pathways by mechanisms such as upregulation of survivin (Park et al, 2004) or constitutive activation of Akt (Decraene et al, 2004). It therefore appears that, despite the accumulation of p53 mutations both prior to and within AK lesions (Backvall et al, 2005), suppression of apoptosis may be a relatively late event in multistage skin carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

et al. 2006

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Inhibitor of differentiation/DNA binding (Id) proteins comprise a class of helix-loop-helix transcription factors involved in proliferation, differentiation, apoptosis, and carcinogenesis. We have shown that while Id2 is induced by UVB in primary keratinocytes, Id3 is upregulated only in immortalized cells. We have now determined that the consequences of ectopic expression of Id3 protein are strikingly different between immortalized and primary keratinocytes. Overexpression of Id3 induces a significant increase in apoptotic cells as revealed by Annexin V positivity as well as proteolytic processing of caspase-3 in immortalized, but not in primary keratinocytes. Id3-green fluorescent protein (GFP)-positive cells exhibited a fivefold increase in apoptotic nuclear fragmentation compared to Id3-GFP-negative cells. These apoptotic responses were accompanied by activation of caspase-3, as shown by immunocytochemical staining with antibodies to active caspase-3. Immunostaining with antibodies to the active form of caspase-9 as well as to the active form of Bax further revealed that induction of apoptosis in Id3-overexpressing keratinocytes occurred via a mitochondrial-caspase-9-mediated pathway. Coexpression of dominant-negative caspase-9 with Id3 significantly suppressed apoptotic nuclear fragmentation, indicating that caspase-9 activation is essential for Id3-induced cell death. This response was also markedly attenuated by coexpression with the Bax antagonist antiapoptotic protein Bcl2, confirming a role for Bax activation in this apoptotic response. Id3-induced Bax activation may result from increased expression of Bax protein. Furthermore, reduction of Id3 expression by small interfering RNAs abrogated the UVB-induced proteolytic activation of caspase-3 in these cells. These data together suggest that UVB-induced apoptosis of immortalized keratinocytes is at least in part due to Id3 upregulation in these cells.

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Expression profiles of p63, p53, survivin, and hTERT in skin tumors

Cited by 66 publications

References 35 publications

Effects of hTERT on metal ion-induced genomic instability

Effects of hTERT on metal ion-induced genomic instability

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

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