NOVEL DELAYED-EARLY AND HIGHLY INSULIN-INDUCED GROWTH-RESPONSE GENES - IDENTIFICATION OF HRS, A POTENTIAL REGULATOR OF ALTERNATIVE PREMESSENGER RNA SPLICING

We have identified 41 novel and many previously known growth response genes induced in regenerating liver and insulin-treated Reuber H35 cel ls, a rat hepatoma cell line that grows in response to physiologic con centrations of insulin and retains some properties of regenerating liv er. Although many genes are expressed similarly in the two systems, th ere are important differences in the kinetics of induction of some gen es. These differences allowed us to identify and characterize novel ge nes that are highly insulin-induced and expressed as delayed-early gen es in regenerating liver. Sequence analysis of CL-6, the most abundant insulin-induced gene, resulted in the identification of a highly hydr ophobic hepatic protein. Sequence analysis of HRS, a highly insulin-in duced delayed-early gene, demonstrated that it is a member of the fami ly of regulators of alternative pre-mRNA splicing. Different forms of HRS mRNA are temporally regulated during the growth response, suggesti ng that HRS could autoregulate processing of its pre-mRNA. Given the d ramatic increase in RNA production during late G1, proteins induced by mitogens like insulin that control RNA processing are likely to have important roles in cell cycle regulation.