Sari, Sibel; (2021) Phenotypic characterization of SHOC2 inactivation in adult mice. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The RAS/RAF/MEK/ERK signaling pathway plays an important role throughout mammalian development, from embryogenesis to tissue-specific cellular homeostasis and its aberrant activation is a major driver of human cancer. RAF activation is a complex process that involves multiple regulatory steps in addition to RAS binding. Key among them is the dephosphorylation of a conserved inhibitory site by a phosphatase complex comprised of SHOC2, MRAS and PP1 (SHOC2 complex). In order to study the role of Shoc2 in vivo, we have generated two mouse models of conditional Shoc2 inactivation. Shoc2 knock-out (KO) and knock-in (KI) mice are embryonic lethal indicating Shoc2 function is required during mouse development. To examine Shoc2 function in adult tissue homeostasis, Shoc2 KO and KI mice were crossed with animals carrying an inducible ubiquitously expressed CreERT2 recombinase. Treatment with tamoxifen leads to efficient recombination in all tissues examined, except brain. Significantly, Shoc2 inactivation is tolerated well in the short term although, pleiotropic phenotypes do emerge after sustained Shoc2 inhibition. Histopathological analysis revealed that Shoc2 KO and KI mice display skin dermatitis characterized by marked inflammation, epidermal hyperproliferation and keratinocyte differentiation defects, as well as hair cycle impairment. Post-mortem studies also show those mice have splenomegaly and lymphadenopathy which could be secondary to the progressively more severe skin inflammation. Male KO mice also have enlarged bladders full of urine suggesting a sexually dimorphic role for Shoc2 in urinary function. Collectively, our results help validate SHOC2 as a therapeutic target for RAS-driven cancers and suggest that future SHOC2 targeted therapies may be tolerated relatively well-compared to other core components of ERK-pathway. However, our studies also indicate that sustained inhibition may lead to toxicities and underscore the importance of optimizing treatment windows as well as close monitoring of some, particularly sensitive tissues.

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