Although TSC1 and TSC2 themselves are tumor suppressors, the TSC complex is often functionally inactivated in cancer through mutations in upstream oncogenes and tumor suppressors, thus providing the most frequent route of mTORC1 activation in cancer. 4 The tuberous sclerosis complex (TSC) protein complex, comprising TSC1, TSC2 and TBC1D7, is an essential negative regulator of mTORC1. ![]() 1, 2, 3 The activation of mTORC1 drives growth-promoting anabolic processes, including a coordinated increase in the synthesis of proteins, lipids and nucleotides. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a critical convergence point for the most common oncogenic signals, leading to aberrant, growth factor-independent activation of mTORC1 signaling in the majority of human cancers. These data expose a therapeutic vulnerability in regulation of the apoptotic machinery downstream of mTORC1 that promotes a cytotoxic response to rapamycin. The BCL-2/BCL-X L inhibitor ABT-263 synergizes with rapamycin to induce apoptosis in TSC-deficient cells and in a mouse tumor model of TSC, resulting in a more complete and durable response. In TSC2-deficient cells and tumors, we find that mTORC1 inhibitors shift cellular dependence from MCL-1 to BCL-2 and BCL-X L for survival, thereby altering susceptibility to BH3 mimetics that target specific pro-survival BCL-2 proteins. We sought to determine the effects of mTORC1 on the core regulators of intrinsic apoptosis. Clinically approved mTORC1 inhibitors, such as rapamycin, elicit a cytostatic effect that fails to eliminate tumors and is rapidly reversible. It consists of 1 video and 6 images.MTORC1 is aberrantly activated in cancer and in the genetic tumor syndrome tuberous sclerosis complex (TSC), which is caused by loss-of-function mutations in the TSC complex, a negative regulator of mTORC1. The piece was submitted to the medium: Design (Pharmaceutical) within the entry type: Direct-to-Consumer - Unbranded and the category: Digital / Mobile. This 2023 Clio Health Gold winning entry titled 'Eyedar' was entered for Horizon Therapeutics by Area 23, an IPG Health Company, New York. ![]() Justine Pujo / Area 23, an IPG Health Companyīill Hanff / Area 23, an IPG Health Companyįrank LaPort / Area 23, an IPG Health Companyīrian Binns / Area 23, an IPG Health Company Sam Astigarraga / Area 23, an IPG Health CompanyĮVP, Group Director, Integrated Production Jessica Haselkorn / Area 23, an IPG Health CompanyĪnna Lopez / Area 23, an IPG Health Company Lauren Dellaquila / Area 23, an IPG Health Company Jeff Halpin / Area 23, an IPG Health Company Jake Moon / Area 23, an IPG Health Company Sydney McElwee / Area 23, an IPG Health Company ![]() Stefan Hanley / Area 23, an IPG Health Company ![]() Rosie Mossey / Area 23, an IPG Health Companyĭenise Bankson / Area 23, an IPG Health Companyĭane Lund / Area 23, an IPG Health CompanyĬaitlin Workman / Area 23, an IPG Health Company Jason Graff / AREA 23, an IPG Health Companyĭavid Adler / AREA 23, an IPG Health Companyįranklin Williams / Area 23, an IPG Health CompanyĪaron Stack / Area 23, an IPG Health CompanyĮduardo Tavares / Area 23, an IPG Health Company Tim Hawkey / AREA 23, an IPG Health Company
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