TRANSGLUTAMINASE 2 CONTRIBUTES TO A P53-DEPENDENT AUTOPHAGY PROGRAM TO SUPPRESS ONCOGENIC TRANSFORMATION

Abstract

THE TUMOR SUPPRESSOR GENE P53 PROTECTS CELLS FROM MALIGNANT TRANSFORMATION, AND OVER HALF OF ALL HUMAN TUMORS HAVE ACQUIRED MUTATIONS THAT INACTIVATE P53. HOWEVER TUMORS WITH WILD-TYPE P53 OFTEN ACCUMULATE OTHER ALTERATIONS WITHIN THE P53 SIGNALING PATHWAY TO PROMOTE TUMORIGENESIS. TO IDENTIFY NEW COMPONENTS OF THIS PATHWAY, WE PERFORMED A LOSS-OF-FUNCTION SCREEN FOR GENES WHOSE IMPAIRMENT DEBILITATE P53 FUNCTIONS AND ENABLED ONCOGENIC TRANSFORMATION OF HUMAN MAMMARY EPITHELIAL CELLS (HMECS) EXPRESSING HTERT, SV40 SMALL T ANTIGEN AND ONCOGENIC RASV12 IN THE PRESENCE OF WILD-TYPE P53. WE IDENTIFIED TRANSGLUTAMINASE 2 (TGM2) AS A PUTATIVE TUMOR SUPPRESSOR AND A NOVEL COMPONENT IN THE P53 PATHWAY. TGM2 SUPPRESSED COLONY FORMATION OF HMECS IN SOFT AGAR AND TUMOR FORMATION IN A XENOGRAFT MOUSE MODEL. THE DEPLETION OF GROWTH SUPPLEMENTS IN CELL CULTURE INDUCED BOTH TGM2 EXPRESSION AND AUTOPHAGY IN A P53-DEPENDENT MANNER, AND TGM2 PROMOTED AUTOPHAGIC FLUX BY ENHANCING AUTOLYSOSOME CLEARANCE.