The Intracellular Tyrosine Kinase Brk Sensitizes Nontransformed Cells to Inducers of Apoptosis

Abstract

The intracellular tyrosine kinase Brk is expressed in regenerating epithelial tissues withhighest levels in the gastrointestinal tract and skin. In these tissues, Brk is restricted to epithelialcells that are exiting the cell cycle and undergoing terminal differentiation. While not expressedin mammary gland, Brk expression is often induced in primary breast tumors and breast tumorcell lines. To identify potential oncogenic functions of Brk, we utilized the immortalized Rat1arat fibroblast cell line that is highly sensitive to transformation. We generated Rat1a cell linesthat stably overexpress wild-type and activated Brk, and we analyzed their growth properties andability to undergo apoptosis in response to stress and DNA damage. Overexpression of Brk didnot induce anchorage-independent growth, and no changes in cell morphology or cell cycleprogression were observed. However, when constitutively expressed, Brk sensitized Rat1a cellsto a variety of apoptotic stimuli including serum deprivation and a combination of UV irradiationand serum starvation. These findings indicate that Brk does not promote proliferation ofnontransformed cells, but plays a positive role in the regulation of the apoptotic response toDNA-damage and stress.