While in the program of studying signaling by p21Ras, we discovered discrete anti-proliferative effects of p21Ras . A single of those properties certainly is the activation of apoptotic signaling, leading to quick cell death, unless of course balanced by a simultaneous and independent activation of survival pathways . This Ras-generated apoptotic signaling particularly involves PKC| activity . In contrast, PKC| is just not normally expected for growth or survival of ordinary tissues. While we initial found these anti-proliferative actions of p21Ras as properties of activated, oncogenic Ras, we have extra not long ago shown that supra-physiological activation of endogenous c-Ras, or activation of selected Ras downstream effector pathways, may even sensitize cells to Ras-mediated apoptosis. Specifically, aberrant signaling upstream of Ras , or aberrant activation of Ras downstream pathways , is sufficient to sensitize cells to apoptosis when PKC| is suppressed .
Carcinoid and also other neuroendocrine tumors within the bronchopulmonary/gastrointestinal tract share many exactly the same genetic abnormalities as adenocarcinomas . These abnormalities comprise activation of Ras straight Raf Inhibitor by mutations, indirectly by loss of Rasregulatory proteins just like NF-1, or through constitutive activation of development element receptors upstream of Ras or downstream effector pathways of Ras, which include PI3K and Raf/MAP kinase. Activation of H-Ras and Ki-Ras are detected in a major fraction of carcinoid and various gastrointestinal neuroendocrine tumors . Ras is usually activated in neuroendocrine tumors by either point-mutation , constitutive signaling from upstream receptor tyrosine kinases, or loss of regulators of Ras, for example RassF1A or NF-1 .
The Her-2/Neu tyrosine kinase receptor, which lies upstream of Ras, is amplified in as much as 40% of gastric carcinoids, and could identify much more aggressive tumor varieties . The Raf/mitogen-activated protein kinase is observed to get aberrantly activated inside a fraction of neuroendocrine tumors. Activating mutations of B-Raf itself are found in some Rosuvastatin neuroendocrine tumors, but infrequently in carcinoid tumors . In these situations the place activating point-mutations of Raf aren’t observed, nonetheless, activation of Raf and/or the Raf-substrate MAP kinases right downstream of Raf, is frequent . This activation in the Raf/MAP kinase pathway may well have a causative purpose in the development of neuroendocrine tumors, independent of point-mutations in B-Raf or Ras . The PI3K pathway may be activated in neuroendocrine tumors by deletion from the tumor suppressor gene PTEN .
Reduction of PTEN in neuroendocrine tumors increases in frequency together with the reduction of differentiation while in the tumor , and reduction of PTEN expression could possibly represent an important step in the progression of neuroendocrine tumors .