The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity

During the last 10 years, multiple signal transduction pathways within cell s have been discovered. These pathways have been linked to the regulation o f many diverse cellular events such as proliferation, senescence, different iation and apoptosis. This review will focus upon the many roles of signali ng by the p42/p44 mitogen-activated protein (MAP) kinase pathway. Recent ev idence suggests that signaling by the MAP kinase pathway can both enhance p roliferation by increased expression of molecules such as cyclin D1, but al so cause growth arrest by increased expression of molecules such as the cyc lin kinase inhibitor protein p21(Cip-1/MDA6/WAF1). These differential effec ts on growth have been correlated to the amplitude and duration of the MAP kinase activity signal. Furthermore several laboratories are reporting data suggesting that inhibition of the MAP kinase pathway, as well as a family of upstream MAP kinase activators, the protein kinase C family, represent a n important route to both radio- and chemo-sensitization of tumor cells. He rein, we describe the historical discovery and characterization of the MAP kinase pathway. In addition we describe potential mechanisms by which inhib ition of protein kinase C, the MAP kinase pathway, and potentially Of p21(C ip-1/MDA6/WAF1) expression, may alter the sensitivities of leukemic and car cinoma cells to cytotoxic insults, leading to increased apoptosis and toss of clonogenicity.