Cytoskeletal proteins are conventionally thought to be conserved, yet evolutionary diversification in the form of gene-family expansions and accelerated amino-acid substitutions are unexpectedly found among actins and tubulins in mammals, including humans. Expression of divergent cytoskeletal proteins is restricted to the testis, but these genes are frequently mis-expressed in cancers. I identified six testis cytoskeletal proteins that appear to play prominent roles in cancer biology as: high expression is prognostic for low probability of survival; many of their encoding genes are mutated, amplified, or deleted in several c...

Read More

Cytoskeletal proteins are conventionally thought to be conserved, yet evolutionary diversification in the form of gene-family expansions and accelerated amino-acid substitutions are unexpectedly found among actins and tubulins in mammals, including humans. Expression of divergent cytoskeletal proteins is restricted to the testis, but these genes are frequently mis-expressed in cancers. I identified six testis cytoskeletal proteins that appear to play prominent roles in cancer biology as: high expression is prognostic for low probability of survival; many of their encoding genes are mutated, amplified, or deleted in several cancers, sometimes rivaling other well-studied oncogenes; and one gene clearly promotes tumor growth.

Our research strategy will be to leverage my background in biochemistry, evolution, and cell biology to systematically probe the basic biology of these proteins in the testis, while determining their roles in cancer. We will define the evolutionary histories of these proteins and correlate hotspots of selective pressure to mutations found in cancer, determine where these proteins localize in their normal environment, and measure their potential to impact the polymerization dynamics of canonical actin and tubulin (Aim 1). We next will examine how these proteins impact cancer cell division, proliferation, and migration. Given the efficacy of cancer drugs targeting microtubules (e.g., taxol), we will design inhibitors that are specific for divergent tubulins mis-expressed in cancers (Aim 2). Finally, we will characterize an array of other testis cytoskeletal genes that are mis-expressed in cancer with the ultimate goal of designing therapeutics to target these entities (Aim 3).

Read Less