AMBRA1 Acts as Tumor Suppressor by Regulating D Cyclins

Researchers from NYU Grossman School of Medicine have found that an enzyme called AMBRA1 prevents cancer by enabling the breakdown of proteins that drive cell growth, and that causes cancer when disabled. Their findings were published today in Nature. 

"Our study clarifies basic features of human cells, provides insights into cancer biology, and opens new research avenues into potential treatments," says corresponding study author Michele Pagano. The authors found that AMBRA1, as a ligase, attaches molecular tags to all three D-type cyclins, labeling them for destruction. The new work also revealed the role of AMBRA1 in development. Mice lacking the AMBRA1 gene, which codes for the AMBRA1 enzyme, developed uncontrolled, lethal tissue growth that distorted the developing brain and spinal cord. The researchers also found for the first time that treating with a CDK4/6 inhibitor pregnant mice carrying embryos without the AMBRA1 gene reduced these neuronal abnormalities.

To confirm the role of AMBRA1 as a tumor suppressor, the scientists monitored cancer cell growth in mouse models of diffuse large B-cell lymphoma, in collaboration with study author Luca Busino. When human B-cell lymphoma cells were transplanted into mice, for instance, tumors without the AMBRA1 gene grew up to three times faster than those with the gene. D-type cyclins are known to assemble with CDK4 and CDK6 into enzymes that encourage both normal and abnormal cell growth. Drugs that inhibit CDK4 and CDK6 have been FDA-approved in recent years as cancer therapies, but some patients have a weaker response to the drugs.

Providing insight into this problem, the current team found that lymphomas lacking AMBRA1 are less sensitive to CDK4/6 inhibitors. When the AMBRA1 gene is missing, levels of D-type cyclins become high enough to form complexes with another CDK (CDK2), which, due to its structure, cannot be inactivated by CDK4/6 inhibitors.