ACTIVATION OF THE TRANSCRIPTION FACTOR GLI1 AND THE SONIC HEDGEHOG SIGNALING PATHWAY IN SKIN TUMORS

Sporadic basal cell carcinoma (BCC) is the most common type of maligna nt cancer in fair-skinned adults. Familial BCCs and a fraction of spor adic BCCs have lost the function of Patched (Ptc), a Sonic hedgehog (S hh) receptor(1-3) that acts negatively on this signalling pathway. Ove rexpression of Shh can induce BCCs in mice(4). Here we show that ectop ic expression of the zinc-finger transcription factor Gli1 in the embr yonic frog epidermis results in the development of tumours that expres s endogenous Gli1. We also show that Shh and the Gli genes are normall y expressed in hair follicles, and that human sporadic BCCs consistent ly express Gli1 but not Shh or Gli3. Because Gli1, but not Gli3, acts as a target and mediator of Shh signalling(5), our results suggest tha t expression of GLi(1) in basal cells induces BCC formation. Moreover, loss of Ptc or overexpression of Shh cannot be the sole causes of Gli 1 induction and sporadic BCC formation, as they do not occur consisten tly. Thus any mutations leading to the expression of Gli1 in basal cel ls are predicted to induce CC formation.