An intracellular protein previously known to transport molecules to and from various cellular organelles in the normal cells may also cause cancer development by interfering with an important growth-control pathway.
Mutation of RAB35 as a stimulus for cancer
The Institute of Whitehead and Memorial Sloan-Kettering Cancer Center conducted an in-depth research on cell signaling pathway regulators including PI3K/AKT that promotes cell division and inhibits apoptosis. The researchers found maximum activity of these regulators in cancer cells and particularly the role of protein RAB35 in cancer formation. An online journal “Science” published their study findings.
According to Douglas Wheeler, A former science student in the lab of David Sabatini, a Whitehead member, and the lead author of the study, although the PI3K/AKT activation leading to tumor formation invariably follows this pathway, a significant number of PI3K/AKT activation can occur without the mutation.
It was obvious that any new regulator was involved in the pathway. Researchers found the wild-type RAB35 to be that sought-after regulator in the PI3K/AKT pathway signaling. Mutation of RAB35 causes up-regulation of P13/AKT that can convert normal cells into malignant.
Wheeler and his team used RNA interference (RNAi) screen to locate genes regulating the pathway with special attention to RAB35. The screen detected some new genes in addition to several previously known genes that appeared to regulate the pathway. A database of mutated genes seen in human cancer cells was then compared with these regulators. To find any similarity, the list of regulators was narrowed down to just 26 from a huge 7,500 regulators.
Wheeler stated that although human cancer cells rarely exhibit RAB35 mutations, they act as true driver mutations whenever exist in tumors. He added that the precise mechanism of malignant transformation might be associated with the activation of a key signaling pathway by a change in the behavior of certain growth factor receptors.
The opinion of Wheeler, a postdoctoral fellow at Broad Institute and the Dana-Farber Cancer Institute, that the mechanism is attractive, should be reliable and thought-provoking.
He states that in this mechanism RAB35 internalizes the receptor and activates the pathway. The dysregulated membrane trafficking then plays a crucial role in cancer development.
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References : New role for an old protein: cancer causer, September 3, 2015