Journal Club: Cancer Biology, Biochemistry & Cancer Biology, Infectious Disease and Immunology

Graduate Division

CANCER BIOLOGY: The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Bell, R.J., et al. (Costello, J.F.). Science. 2015. Epub ahead of print.

In normal cells, the number of cell divisions is usually limited by the need for chromosomes to be capped with protective telomeres, which shorten with each division. Cancer cells find a way around this block, often by activation of TERT, the enzyme that can extend telomeres.

Previous research on several types of cancer frequently found two particular mutations in the TERT promoter, but the specific effect of these mutations was unknown. Here, Bell and colleagues show that these mutations allow recruitment of the transcription factor GABP to the TERT promoter, leading in turn to TERT expression.

They find this recruitment in four different cancer types. They also observe that multiple ETS motifs located near these TERT promoter mutations cooperate to activate TERT; they hypothesize that the ETS motifs stabilize GABP binding.

BIOCHEMISTRY & CANCER BIOLOGY: Structures for human phosphofructokinase-1 and atomic basis of cancer-associated mutations. Webb, B.A., et al. (Barber, D.L.). Nature. 2015. Epub ahead of print.

The glycolytic pathway, subject of a thousand undergrad biochemistry quizzes, is regulated most strongly by the activity of phosphofructokinase-1, whose activity is affected by binding of many metabolites. PFK1 is thought to have an important role in metabolic changes in cancer cells.

In this paper, the authors present the first crystal structure of tetrameric PFK1, specifically the human platelet isoform PFKP, in complex with ATP-Mg2+ and with ADP.

By comparing the structures, they were able to determine that there is a large conformational change upon ATP hydrolysis to ADP, one effect of which is that the catalytic site becomes more open. They also examined the effect of three mutations seen in cancer and found that they alter how binding of certain metabolites to PFKP alters its activity.

INFECTIOUS DISEASE: FCRL5 delineates functionally impaired memory B cells associated with Plasmodium falciparum exposure. Sullivan, R.T. et al. (Greenhouse, B.). PLoS Pathog. 2015. 11(5):e1004894.

The protozoan Plasmodium falciparum is the most virulent cause of malaria. Although there has been significant progress in preventing and treating malaria, with annual deaths down about 50 percent since 2000, it still kills hundreds of thousands of people each year.

People infected with P. falciparum tend to have atypical memory B cells, but little careful study of these B cells had been done. Here, Sullivan and colleagues provide new insights into these cells.

They found that these B cells had decreased expression of B cell receptor compared to normal memory B cells. They further found that they tended to express high levels of FCRL5, expression of which correlated with poor antibody production after the cells were stimulated. Moreover, higher levels of P. falciparum exposure correlated with having more FCRL5-expressing B cells.

IMMUNOLOGY: The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway. Sjölin-Goodfellow, H., et al. (Weiss, A.). Sci Signal. 2015. 8(377):ra49.

The T cell receptor binds to a peptide presented by an MHC receptor on another cell. Binding of this peptide-receptor complex to the T cell receptor initiates a carefully regulated signaling pathway, two early steps of which are activation of the kinase Lck followed by ZAP-70.

In this paper, the Weiss lab provides new insight into how ZAP-70 activity helps tune this signaling pathway. They used mass spectrometry-based techniques to carefully profile the phosphorylation state of cellular proteins over time in the presence and absence of ZAP-70 catalytic activity.

They found that ZAP-70 stimulates negative feedback on Lck. They also created a computer model to explain their experimental results, predicting a particular order of tyrosine phosphorylation events on the TCR ζ protein.