[Oncogenic activation of p21(ras) and pp60(c-src) in human colonic Caco-2 cells decreases insulin receptor function and expression through protein kinase C-dependent and independent pathways].
In view of the potent mitogenic effect exerted by insulin in human colonic cells, we used Caco-2 cells transfected with an activated (Val12) human Ha-ras gene or the polyoma middle T (PyMT) oncogene, a constitutive activator of pp60c-src tyrosine kinase activity, to investigate the effect of oncogenic p21ras and PyMT/pp60c-src on insulin mitogenic signaling. As compared to vector control Caco-2 cells, both oncogene-transfected cells exhibited: 1) a lost of response to insulin's stimulatory effect on mitogen-activated protein (MAP) kinase activity and cell proliferation, both of which were constitutively increased; 2) a decrease in insulin receptor (IR) affinity and insulin-stimulated exogenous tyrosine kinase activity, which resulted, at least in part, from increased protein kinase C (PKC) activity (4), since both IR alterations were partially corrected by PKC down-regulation; and 3) a decrease in both insulin receptor mRNA level and insulin receptor number, which was independent of PKC since it persisted after PKC down-regulation. In conclusion, oncogenic p21ras and PyMT/pp60c-src abolished insulin mitogenic signaling in Caco-2 cells through mechanisms involving (i) constitutive activation of MAP kinase, and (ii) marked decreases in both insulin receptor function and expression which were mediated by PKC-dependent and PKC-independent pathways respectively. This is the first evidence that, when oncogenically activated, p21ras and pp60c-src not only exert a negative control on insulin receptor function but also repress insulin receptor gene expression in human colonic cells.
Baron-Delage
S
S
Laboratoire de biologie cellulaire, Inserm U402, faculté de médecine Saint-Antoine, Paris, France.
Barbu
V
V
Bertrand
F
F
Chastre
E
E
Lévy
P
P
Gespach
C
C
Capeau
J
J
Cherqui
G
G
D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008938:Mitosis / Q000502:physiology; D015689:Oncogene Protein p21(ras) / Q000235:genetics* / Q000378:metabolism; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000378:metabolism
D011972:Receptor, Insulin; D015688:Oncogene Protein pp60(v-src); D011493:Protein Kinase C; D015689:Oncogene Protein p21(ras)
L'activation oncogénique de p21(ras) et pp60(c-src) dans les cellules coliques humaines Caco-2 diminue la fonction et l'expression du récepteur de l'insuline par des voies dépendante et indépendante de la protéine kinase C.