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Review
. 2010 Apr;22(2):226-33.
doi: 10.1016/j.ceb.2009.11.003. Epub 2009 Nov 28.

Autophagy genes as tumor suppressors

Chengyu Liang  1 , Jae U Jung
Affiliations
Review

Autophagy genes as tumor suppressors

Chengyu Liang et al. Curr Opin Cell Biol. 2010 Apr.

Abstract

Autophagy, originally described as a universal lysosome-dependent bulk degradation of cytoplasmic components upon nutrient deprivation, has since been shown to influence diverse aspects of homeostasis and is implicated in a wide variety of pathological conditions, including cancer. The list of autophagy-related (Atg) genes associated with the initiation and progression of human cancer as well as with responses to cancer therapy continues to grow as these genes are being discovered. However, whether Atg genes work through their expected mechanisms of autophagy regulation and/or through as-yet-undefined functions in the development of cancer remains to be further clarified. Here we review recent advances in the knowledge of the molecular basis of autophagy genes and their biological outputs during tumor development. A better understanding of the mechanistic link between cellular autophagy and tumor growth control may ultimately better human cancer treatments.

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Figures

Figure 1
Figure 1. Schematic representation of the autophagy pathway and its regulation by both oncogenic and tumor suppressive signaling
The induction of autophagy by various stimuli (e.g. starvation, hypoxia, etc) signals through the activation of the TSC1/TSC2 complex that leads to the inhibition of mTOR. Dephosphorylated mAtg13 resulting from mTOR inactivation then associates with and activates the Atg1/ULK kinase. Together, they form the Atg1 kinase complex with FIP200 and Atg101, triggering the autophagic cascade. Vesicle nucleation is primarily driven by the class III phosphatidylinositol (PtdIns) 3-kinase (PI3KC3) complex. The core subunits of this complex include PI3KC3, p150, and Beclin1. Recent data suggest that mulitple Beclin1 complexes may be involved in the mammalian autophagy regulation. In pariticular, the tumor suppressor, UVRAG, Bif-1 (an UVRAG interactor), and probably Ambra-1 associate with Beclin1 to activate autophagy. This is frequently dysregulated in many human cancers. Additionally, Atg14 was also found to promote atuophagy by forming a separate complex with Beclin1. The anti-apoptotic Bcl-2 proteins negatively regulate autophagy by sequestering Beclin1. This is counteracted by the proapoptotic BH3-only molecules which promote autophagy by freeing Beclin1 from Bcl-2 inhibition. Two ubiquitin-like conjugation systems are involved in autophagosomal membrane expansion and completion: one is the Atg8/LC3-phosphatidylethanolamine (PE) conjugation, the other is the Atg12-Atg5-Atg16 conjugation. After proteolytic cleavage of its carboxyterminus by the Atg4C cystein protease, Atg8 is coupled to the membrane lipid PE after sequential processing by Atg7, an E1-like enzyme and Atg3, an E2-like enzyme. Atg12 is conjugated to Atg5 in a similar manner except Atg10 is used as the E2 enzyme instead of Atg3. During this conjugation process, the interation of ubiquitin-like Atg8 with Atg3 can be severely disturbed by FLIP, an oncogenic protein. In contrast, proapoptotic DAPK positively regulates this process by associating with an Atg8/LC3-interacting cytoskeleton molecule, MAP1B. The fusion of the autophagosome with the lysosome signifies the maturation stage of the autophagy pathway, a step that is least understood but has been found to functionally converge with the endocytic pathway. Lysosomal fusion is driven by SNAREs, the small GTPase Rab7, PI3KC3, and the HOPS complex which consists of the class C vacuolar protein sorting (C/Vps) complex core (Vps11, Vps16, Vps18, and Vps33) and two additional subunits Vps39 and Vps41 [–80]. UVRAG forms a complex with HOPS and facilitates HOPS-mediated membrane tethering, which likely involves Rab7 activation. In addition, Rubicon was recently found to associate with the endosome-associated PI3KC3 complex, exerting an inhibitory effect on the PI3KC3 activity and the fusion of the autophagosome with the lysosome. Not only are effector proteins of autophagy implicated in cancer development, but the autophagy pathway is also regulated by both oncogenes and tumor suppressors.
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