**13.1. Tumour suppressor genes that regulate autophagy**

To date, several tumour suppressor proteins that regulate autophagy have been described. These include: Beclin 1, UV irradiation-resistance-associated gene (UVRAG), PTEN, Bcl-2, and p53. The majority of them act as autophagy inducers with the exception of p53 that is able to activate or inhibit autophagy.

*Role of Beclin 1 in autophagy:* Beclin1 is a key regulator of autophagy. It regulates the autophagic process at different levels by combining with the enzyme class III PI3K (PI3KC3) and specific group of proteins forming unique class III PI3K-Beclin complexes. This PI3KC3- Beclin complex functions as a core complex during autophagy [136,137] by phosphorylating phosphatidylinositol to produce phosphatidylinositol 3-monophosphate, which presumably allows the recruitment of essential autophagy related (Atg) proteins to the membrane. In mammals, at least three types of class III PI3-kinase-Beclin complexes contribute to autophagy [84,138,139].

*Role of Beclin 1 in tumour suppression vs. autophagy:* The first link between autophagy and cancer was established in 1999, when Liang and colleagues discovered that the autophagic protein Beclin 1 was able to inhibit tumourigenesis [140]. Beclin 1 is a tumour suppressor gene [141,142] monoallelically deleted in many types of cancers, including ovary (75%), breast (50%) and prostate (40%). Several studies suggest that the activation of autophagy by Beclin 1 is tightly associated with its tumour suppression function. For example, overexpression of Beclin-1 in the human MCF-7 breast carcinoma cell line is associated with inhibition of cell proliferation and induces autophagy [140]. In contrast, studies *in vivo* demonstrate that the monoallelic disruption of Beclin 1 gene promotes cellular proliferation and reduces autophagy [142]. Furthermore, genetically engineered mouse models with heterozygous disruption of Beclin 1 have decreased autophagy and are more prone to develop tumours, including lung carcinomas, hepatocellular carcinomas, lymphomas and mammary precancerous lesions [141,143]. Taken together, these studies firmly support the notion that autophagy induction and tumour inhibition function of Beclin 1 are closely interconnected.

*UVRAG* is another tumour suppressor protein that is able to activate autophagy. UVRAG is a positive regulator of Beclin 1, as it promotes its binding to PI3KC3 to form the complex and enhance Beclin 1 activity. Through mediating Beclin 1-PI3KC3 complex, UVRAG can promote autophagy, thus inhibiting carcinogenesis of human colon cancer cells. It has also been proposed that UVRAG is involved in causing membrane curving [144]. Furthermore, the monoallelic deletion or mutation of UVRAG has been observed in several human cancers such as colon, gastric and breast cancer [145-147].

*Bif-1* is also a tumour suppressor that promotes autophagy. Similar to UVRAG, Bif-1 is a positive regulator of Beclin 1, as it enhances its interaction with PI3KC3, thus increasing autophagy. Consistently, it has been shown that loss of Bif-1 prevented the formation of autophagosomes and induced the development of spontaneous tumours in mice [144]. Furthermore, expression of Bif-1 is significantly reduced in prostate, colon, urinary bladder and gastric tumours [146,148,149]. The precise mechanism of Bif-1 in suppressing tumourigenesis has not been fully clarified, but it is reasonable to presume that its tumour inhibitory activity is associated with its role in inducing autophagy. Some groups have also suggested that Bif-1 suppresses tumour growth through its interaction with proapoptotic Bax [150].
