The retinoblastoma protein is an important tumor suppressor due to its role in cell cycle control. University of Illinois Cancer Center member Maxim Frolov has discovered another function.
In a new paper published in Cell Reports, Frolov, PhD, professor of biochemistry and molecular genetics in the University of Illinois College of Medicine, has found that retinoblastoma protein (pRB) has an important function in skeletal muscle.
“Our research led to two important findings,” Frolov said. “First, we found that pRB activates the myogenic transcriptional program during muscle development. Secondly, we show that in its absence muscle growth is severely reduced.”
The retinoblastoma protein is mutated or functionally inactivated in nearly all human cancers, Frolov said. The best-known function of pRB is to promote exit from the cell cycle. As normal cells exit cell cycle, they undergo differentiation, a series of events to become specialized cells such as those of skin, bone or muscle. Although pRB has been shown to promote cell differentiation in cell-based models, whether pRB works in the same way during animal development is unknown, he said. This is because differentiation defects in pRB deficient tissues may be the consequence of defects in cell cycle exit.
“We addressed this issue in fruit flies that share significant similarity in the arrangement of the RB pathway that pRB is a part of,” Frolov said. Maria Paula Zappia, PhD, research assistant professor in Frolov’s lab and the first author on the paper, inactivated pRB in skeletal muscles and found severe defects in muscle growth that were independent of the role of pRB in cell cycle control. The reduced growth is due to pRB being needed to activate the muscle specific transcriptional program.
“Our data show that pRB has a direct role in muscle development that is separate from its known role in cell cycle exit,” Frolov said. These results may have broader implications since the state of differentiation inversely correlates with tumor aggressiveness – poorly differentiated tumors are more aggressive and less amenable to therapies. Thus, inactivation of pRB that is a frequent event in cancers may also directly contribute to the differentiation status in tumors.
Frolov’s laboratory is working to identify specific functions of the RB pathway that are important during normal animal development and why the loss of these functions is one of the key events in cancer. Last year in a paper published in Nature Communications, Frolov and his graduate student, Majd Ariss, described the first cell atlas of a normal eye of a fruit fly and showed how to use single-cell RNA sequencing to profile the impact of an oncogenic mutation such as the loss of pRB on individual cell types in a fruit fly’s developing eye.
Using that approach, the researchers found a small group of cells in the Rb deficient eye that are intrinsically sensitive to apoptosis due to elevated glycolysis and lactate secretion. This illustrates how an oncogenic mutation uniquely interacts with intrinsic cell circuitry. This concept is important in understanding why only certain cells may give rise to cancers that may originate in certain type of cells. For example, retinoblastoma is a rare form of cancer that is believed to originate from cone cell precursors because these cells are uniquely sensitive to Rb loss. It is the most common primary malignant intraocular cancer in children, being almost exclusively found in young children.
Photography by Jenny Fontaine