title: The Retinoblastoma Tumor Suppressor Protein (pRb)/E2 Promoter Binding Factor 1 (E2F1) Pathway as a Novel Mediator of TGFβ-induced Autophagy.
abstract: TGFβ is a multifunctional cytokine that regulates cell proliferation, cell immortalization, and cell death, acting as a key homeostatic mediator in various cell types and tissues. Autophagy is a programmed mechanism that plays a pivotal role in controlling cell fate and, consequently, many physiological and pathological processes, including carcinogenesis. Although autophagy is often considered a pro-survival mechanism that renders cells viable in stressful conditions and thus might promote tumor growth, emerging evidence suggests that autophagy is also a tumor suppressor pathway. The relationship between TGFβ signaling and autophagy is context-dependent and remains unclear. TGFβ-mediated activation of autophagy has recently been suggested to contribute to the growth inhibitory effect of TGFβ in hepatocarcinoma cells. In the present study, we define a novel process of TGFβ-mediated autophagy in cancer cell lines of various origins. We found that autophagosome initiation and maturation by TGFβ is dependent on the retinoblastoma tumor suppressor protein/E2 promoter binding factor (pRb/E2F1) pathway, which we have previously established as a critical signaling axis leading to various TGFβ tumor suppressive effects. We further determined that TGFβ induces pRb/E2F1-dependent transcriptional activation of several autophagy-related genes. Together, our findings reveal that TGFβ induces autophagy through the pRb/E2F1 pathway and transcriptional activation of autophagy-related genes and further highlight the central relevance of the pRb/E2F1 pathway downstream of TGFβ signaling in tumor suppression.
authors.affiliation: From the Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Juliana
authors.initials: J
authors.lastname: Korah
authors.affiliation: From the Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Canaff
authors.affiliation: From the Department of Medicine, McGill University Health Center, Cancer Research Program, Montreal, Quebec H4A 3J1, Canada JJ.Lebrun@mcgill.ca.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lebrun
mesh_terms: D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010588:Phagosomes; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D016207:Cytokines; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D050880:p300-CBP Transcription Factors
keywords: autophagy; cancer; hepatocellular carcinoma; retinoblastoma protein (pRb, RB); transforming growth factor beta (TGF-β); tumor suppressor gene