Endogenous MYC and the molecular clock in cancer
While MYC is mutated, amplified, or translocated in many human cancers, in others it is overexpressed or stabilized downstream of other oncogenic mutations, and the role of MYC in control of the clock in these settings is unknown. For instance, mutated RAS, common in a variety of cancers, prevents MYC protein degradation. Endogenous MYC, unlike mutated MYC, circadian-controlled and oscillates at the mRNA and protein level, so it remains unclear how endogenous MYC stabilized or overexpressed downstream of other oncogenic mutations may affect the molecular clock.
We will utilize knowledge of the extended MYC-protein family to delete negative regulators of MYC activity and to ‘remove the brakes’ on MYC, while keeping it under endogenous control. This will allow us, in a reductionist model, to study the role of hyperactivated endogenous MYC in cancer cell growth and control of the molecular clock, and to contrast it with more classically mutated or overexpressed MYC. These data will help us to better understand the varied roles of MYC in different expression contexts.
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