Several in vitro studies have shown that PHD2 is transiently upregulated in a HIF-dependent manner under normoxic as well as mild hypoxic conditions, which could L-Ornithine suggest that HIF might induce an autoinhibitory Mebhydrolin napadisylate effect on its own activity. Moreover, D��Angelo et al demonstrated that hypoxic upregulation of PHD2 acts as a feedback mechanism to stop hypoxic signalling in reoxygenated cells. Hence, we postulate that the lack of HIF1a in BCC and TE specimens can be explained by the presence of PHD2. Activity of the mTORC1 pathway was assessed by use of the upstream regulator pAKT and downstream target pS6. pAKT was positive in 88?9% of BCC and 87?5% of TE, while 55% of BCC and 61?3% of TE specimens were positive for pS6, supporting the presence of active mTOR signalling. The positive stains for pAKT and pS6 found in our study are consistent with the known activity of PIK/AKT signalling in BCC. In addition, strong expression of pAKT and pS6 has been observed in a variety of skin neoplasms including Bowen��s disease, keratoacanthoma, squamous cell carcinoma and extramammary Paget��s disease. However, despite positive staining of pAKT and pS6, hardly any mTORC1 phosphorylation at Ser2448 was detected in both tumour types. This observation is consistent with two other studies reporting weak positivity of mTOR in only 7?7% of BCC and 36% positivity among 85 epidermal tumours other than BCC. Ser-2448 is the mTORC1phosphorylation site modified either directly by AKT or by the downstream target of mTORC1, p70S6 kinase, making it the most important marker for activation of mTOR. However, the upregulation of up- and downstream target genes of the mTORC1 signalling cascade do suggest activation of downstream mTORC1 signalling components downstream, which could be attributed to PIK- signalling. In addition, it is known that multiple feedback loops exist, for example S6 kinase can dampen growth factor receptor signalling to PI3K. Overall the immunohistochemical analysis is consistent with activity of HIF1 and mTORC1 signalling in both BCC and TE, in addition to the known PIK-AKT activity in BCC.