Molecular basis of pituitary oncogenesis.
Recent advances in the molecular biology has served to unveil the underlying genetic and epigenetic alterations in pituitary adenomas. Three nuclear transcriptional factors, AP-1, CREB, and Pit-1, which are targets of protein kinase C and A, appear to play critical roles in both neoplastic growth and hormone secretion in hormone-producing adenomas. The alteration of G proteins such as Gs and Gi2 is a direct cause of the activation of such transcriptional factors. Autocrine growth factor/cytokine loops also contribute to the augmented signal transductions. Bromocriptine and somatostatin analogs have effects to lower cellular cAMP level through inhibitory G proteins, although the mechanism leading to cellular apoptosis is unknown. On the other hand, most non-functioning adenomas may not have PKC- or PKA-mediated oncogenic mechanisms. Although the loss of Rb and p27Kip1 genes has been demonstrated as a cause of murine pituitary adenomas, the role of tumor suppressor genes for human pituitary adenomas remains elusive. However, potential candidates for the suppressor genes are now emerging. The recently cloned multiple endocrine neoplasia type I gene is one example. Alterations of c-myc/bcl-2, and ras, although rare, appear to be an important cause of the process by which adenoma cells acquire aggressive phenotypes. Further studies on the links between abnormal signal transductions and aberrant tumor suppressor genes will be needed to clarify the whole picture of pituitary oncogenesis.
Tada
M
M
Division of Cell Biology, Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan.
Kobayashi
H
H
Moriuchi
T
T
D000236:Adenoma / Q000235:genetics*; D000818:Animals; D016207:Cytokines / Q000235:genetics; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006133:Growth Substances / Q000235:genetics; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology
D016207:Cytokines; D006133:Growth Substances