The Tumor Suppressor PTEN Positively Regulates Macroautophagy by Inhibiting the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway*

By Sébastien Arico, A. Petiot, C. Bauvy, P. F. Dubbelhuis, A. Meijer, P. Codogno, E. Ogier-Denis. Journal of Biological Chemistry, 2001

597 citations recorded by the source corpus.

The tumor suppressor PTEN is a dual protein and phosphoinositide phosphatase that negatively controls the phosphatidylinositol (PI) 3-kinase/protein kinase B (Akt/PKB) signaling pathway. Interleukin-13 via the activation of the class I PI 3-kinase has been shown to inhibit the macroautophagic pathway in the human colon cancer HT-29 cells. Here we demonstrate that the wild-type PTEN is expressed in this cell line. Its overexpression directed by an inducible promoter counteracts the interleukin-13 down-regulation of macroautophagy. This effect was dependent upon the phosphoinositide phosphatase activity of PTEN as determined by using the mutant G129E, which has only protein phosphatase activity. The role of Akt/PKB in the signaling control of interleukin-13-dependent macroautophagy was investigated by expressing a constitutively active form of the kinase (MyrPKB). Under these conditions a dramatic inhibition of macroautophagy was observed. By contrast a high rate of autophagy was observed in cells expressing a dominant negative form of PKB. These data demonstrate that the signaling control of macroautophagy overlaps with the well known PI 3-kinase/PKB survival pathway and that the loss of PTEN function in cancer cells inhibits a major catabolic pathway.

Subfields: Electrical and Electronic Engineering, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1b4b00fb7e6f96fe6e94b2d2e274ee431d4796f3

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Citations in the corpus

• The role of autophagy in cancer development and response to therapy (2005, background): “PTEN dephosphorylates and thereby inhibits class I PI3K, which suppresses AKT activity and allows autophagy to be initiate”
• An Overview of the Molecular Mechanism of Autophagy (2009, background): “PTEN, a 3′-phosphoinositide phosphatase, antagonizes PKB, and has a stimulatory effect on autophagy (Arico et al. 2001).”
• Eaten alive: a history of macroautophagy (2010, result): “In agreement with these results, overexpression of PTEN, which hydrolyzes PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 , stimulates autophag”
• Regulation and role of autophagy in mammalian cells. (2004, background): “The phosphatase PTEN, which hydrolyzes PtdIns(3,4,5)P 3 (Maehama & Dixon, 1998), has a stimulatory effect on autophagy by relieving the class I PI3K/PKB inhibition ( Arico et al., 2001).”
• Regulation of Autophagy by Reactive Oxygen Species (ROS): Implications for Cancer Progression and Treatment (2009, unknown): “Furthermore, the established tumor-suppressor genes p53 and PTEN are known to induce autophagy (6, 34), whereas the oncogenic proteins Bcl-2 and Bcl-X L interact with Beclin-1 to inhibit autophagy (73, 86).”
• Pathways of apoptotic and non-apoptotic death in tumour cells (2004, background): “, whereas PTEN — a tumour suppressor that negatively regulates PI3K signalling — might normally promote autophag”
• LC3 conjugation system in mammalian autophagy (2004, background): “In contrast to the class 3 PI3kinase, whose activity is essential to autophagy (Ogier-Denis & Codogno, 2003; Kihara et al., 2001), the class 1 PI3 kinase strongly inhibits autophagy (Arico et al., 2001).”
• Autophagy in malignant transformation and cancer progression (2015, unknown): “…tumors cumulatively referred to as PTEN hamartoma tumor syndrome (PHTS) is provoked by germ-line mutations in phosphatase and tensin homolog ( PTEN ), an enzyme that promotes autophagy by functionally antagonizing PI3K signaling (Liaw et al , 1997; Marsh et al , 1997; Arico et al , 2001).”
• Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity (2010, background): “For example, such tumour suppressors as PTEN and TSC1/2 promote autophagy by inhibiting the mTOR signalling pathwa”
• Role and regulation of starvation-induced autophagy in the Drosophila fat body. (2004, background): “Instead, inhibiagy is also suppressed by components of the insulin/tion of autophagy enhances TOR mutant phenotypes, class I phosphoinositide 3-kinase (PI3K) pathway up-including reduced cell size, growth rate, and survival. stream of TOR, including the insulin receptor, PI3K, andThus, in cells lack”
• Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. (2006, background): “AKT activation, which inhibits autophagy (Arico et al., 2001) (Figure 2), or direct downregulation of Beclin1 blocks this survival pathway, stimulating necrotic cell death (Figure 3I).”
• Autophagy: from phenomenology to molecular understanding in less than a decade (2007, result): “In agreement with these results, overexpression of PTEN , which reduces the level of PtdIns(3,4,5)P 3 , stimulates autophag”
• Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG (2006, background): “Conversely, anti-apoptotic signalling pathways (such as PI(3)K–AKT–TOR), suppress autophag”