Research Groups > Recent discoveries
Recent discoveries from our laboratory
Notch signalling prevents chemotherapy-induced apoptosis in breast cancer by activating Akt
The Notch signalling pathways is aberrantly activated in most human breast cancers. Our previous work has shown that this increase in Notch signalling induces a profound resistance to many apoptotic stimuli including chemotherapeutic agents. We have now shown that the apoptotic resistance is due to the activation of Akt by a Notch-induced secreted factor. Akt signalling then prevents the activation of p53 following treatment with DNA-damaging chemotherapeutic agents. Mechanistically this due to the phosphorylation of ASK1 by Akt blocking ASK1/JNK signalling and therefore the JNK mediate phosphorylation and activation of p53.
Elevated EDAR signalling in the mammary gland leads to focal tumours that display extensive squamous metaplasia
EDAR signalling is required for the normal development of several skin appendages, such as hair and teeth. We have recently shown that EDAR signalling plays a significant role in the development of many skin-derived glands including the mammary gland. We have also found that elevated EDAR signalling leads to supernumerary nipples in female mice, ductal development in males, and in focal mammary tumours in breeding female mice. The tumours that develop all display extensive squamous metaplasia. Interestingly, similar phenotypes are seen when Wnt signalling is elevated and EDAR has been shown to regulate Wnt gene expression during hair follicle development.
Dishevelled attenuates Notch signalling by promoting the degradation of RBP‑Jκ
Work in Drosophila has suggested that Dishevelled, a component of the Wnt signalling pathway, can inhibit Notch signalling. We have shown that a similar crosstalk also occurs in vertebrates. Mechanistically the crosstalk is mediated by an interaction between Dishevelled and RBP‑Jκ/CBF1, the transcription factor at the base of the Notch pathway, which promotes the proteosomal degradation of RBP‑Jκ/CBF1.