Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins

Jackson, Sarah; Harwood, Catherine A.; Thomas, Miranda; Banks, Lawrence; Storey, Alan

doi:10.1101/gad.182100

Cited by 292 publications

(245 citation statements)

References 33 publications

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“…The apoptotic response has been extensively studied because elimination of DNA damaged KCs is an efficient and powerful protective mechanism for preventing development of skin cancer (Ziegler et al, 1994). While UV-light exposure triggers an assortment of cellular alterations involving multiple signaling pathways, dissection of the apoptotic response revealed it is principally mediated by mitochondrial dysfunction (Jackson et al, 2000;Nickoloff et al, 2002;Bowden, 2004).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

et al. 2005

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Ultraviolet (UV) light exposure is a common cause of epithelial-derived skin cancers, and the epidermal response to UV-light has been extensively studied using both mouse models and cultured human keratinocytes (KCs). Elimination of cells with UV-induced DNA damage via apoptosis provides a powerful mechanism to minimize retention or expansion of genetically abnormal cells. This cell editing function has largely been ascribed to the biological role of the p53 tumor suppressor gene, as mutations or deletions involving p53 have been linked to skin cancer development. Rather than introducing mutations, or using cells with complete loss of wild-type p53, we used an siRNA-based approach to knockdown, but not eliminate, p53 levels in primary cultures of human KCs followed by UV-irradiation. Surprisingly, when p53 levels were reduced by 50-80% the apoptosis induced by exposure to UV-light was accelerated and markedly enhanced (two-to three-fold) compared to control siRNA treated KCs. The p53 siRNA treated KCs were characterized by elevated E2F-1 levels accompanied by accelerated elimination of the Mcl-1 and Bcl-x L antiapoptotic proteins, as well as enhanced Bax oligomerization. Forced overexpression of either Mcl-1 or Bcl-x L reduced the UV-light enhanced apoptotic response in p53 siRNA treated KCs. We conclude that p53 not only can provide proapoptotic signals but also regulates a survival pathway influencing Mcl-1 and Bcl-x L levels. This overlooked survival function of p53 may explain previous paradoxical responses noted by investigators using p53 heterozygous and knockout mouse models, and opens up the possibility that not all liaisons within the cell involving p53 necessarily represent fatal attractions.

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Section: Introductionmentioning

confidence: 99%

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

et al. 2005

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“…The beta HPV types were first isolated in skin cancer-prone patients suffering from a rare autosomal recessive genetic disorder called epidermodysplasia verruciformis, but it is now clear that they are commonly found in the skin of healthy individuals (Pfister, 2003). Characterization of the biological properties of the products of the early genes E6 and E7 from different beta HPV types in in vitro and in vivo model has highlighted the potential carcinogenicity of these viruses (Jackson et al, 2000;Caldeira et al, 2003;Akgul et al, 2005;Dong et al, 2005;Schaper et al, 2005;Accardi et al, 2006;Michel et al, 2006). We showed that expression of E6 and E7 from the beta HPV38 in primary human keratinocytes results in inactivation of the tumour suppressor p53 and pRb and immortalization (Caldeira et al, 2003;Accardi et al, 2006).…”

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confidence: 99%

Loss of p53 or p73 in human papillomavirus type 38 E6 and E7 transgenic mice partially restores the UV-activated cell cycle checkpoints

et al. 2007

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We have previously shown that human keratinocytes expressing E6 and E7 from the cutaneous human papillomavirus (HPV) type 38 have high levels of a specific form of p53, which in turn activate the transcription of DNp73 gene. Expression of HPV38 E6 and E7 in mouse skin also promotes p53 and DNp73 accumulation. Interestingly, keratinocytes of these mice do not undergo cell cycle arrest after skin ultraviolet (UV) irradiation. Here, we provide several lines of evidence that DNp73 expression and lack of the UV response are directly linked. Loss of p53 gene in HPV38 E6/E7 transgenic mice abolished DNp73 expression and partially restored the UV-activated cell cycle checkpoints. Similarly, loss of p73, and consequently DNp73, led to restoration of the p53 pathways. In fact, keratinocytes of p73 À/À HPV38 E6/E7 transgenic mice upon UV irradiation express high levels of p21 WAF1 and are cell cycle arrested. Thus, HPV38 E6 and E7, via DNp73 accumulation, are able to alter the regulation of cell cycle checkpoints activated by UV radiation. These data suggest that UV and HPV may cooperate in skin carcinogenesis.

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“…Bax mutations have been detected in leukemias, gastrointestinal and colorectal cancer (Rampino et al, 1997;Zhang et al, 2000). Abrogation in Bax and Bak protein expression has been observed in skin, gastric and colorectal cancer (Rosen et al, 1998;Jackson et al, 2000). Deregulation in the p53 pathway seems to be an important target in the development of colorectal cancer, and it is of great interest to investigate whether mutations in Noxa are present in colorectal cancer, and whether the levels of mRNA and protein expression are of importance.…”

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confidence: 99%

Noxa in colorectal cancer: a study on DNA, mRNA and protein expression

et al. 2003

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Noxa is a BH3-only member of the Bcl-2 family, upregulated by p53 as a response to DNA damage. Mutations in the BH3-only region of other BH3-only members lead to an inactive protein. We have investigated the mRNA expression of Noxa with real-time PCR in 94 unselected colorectal adenocarcinomas and the corresponding normal mucosa. Among them, Noxa protein expression was investigated with immunohistochemistry in 16 tumors and six corresponding normal mucosa samples. Further, we searched for Noxa mutations in all the cases using single-stranded conformation polymorphism and DNA sequencing. The mRNA expression of Noxa was weak in 9% and strong in 2% of the tumors, and decreased in 9% and increased in 16% of the tumors compared with the normal mucosa; however, these changes did not have any clinical or pathological significance. The protein level in most of the cases investigated was correlated with the mRNA level. We did not find any mutations in the Noxa gene. Thus, we suggest that Noxa may not be of importance in the development of colorectal cancer.

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Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins

Cited by 292 publications

References 33 publications

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

Loss of p53 or p73 in human papillomavirus type 38 E6 and E7 transgenic mice partially restores the UV-activated cell cycle checkpoints

Noxa in colorectal cancer: a study on DNA, mRNA and protein expression

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