TUMOR ENDOCRINOLOGY PROJECT

20.TUMOR ENDOCRINOLOGY PROJECT

    The Tumor Endocrinology Project aims at the clarification of the pathophysiology of cancer patients leading to the development of new methods for diagnosis and treatment. Tumor development involving endocrine tissues and receptors, pathogenesis of cancer cachexia, and protection of neuroendocrine cells from toxic proteins are currently studied.
Multiple Endocrine Neoplasia Type 1 and Other Heritable Endocrine Diseases

    Multiple endocrine neoplasia type 1 is a familial cancer syndrome characterized by the simultaneous occurrence of various endocrine tumors. Germline and somatic mutations of the responsible gene MEN1 in patients with this syndrome and related disorders have been analyzed in collaboration with regional hospitals, and revealed novel pathogenic mutations.
    The molecular function of menin, the protein product of the MEN1 gene, is unknown. Nm23, a protein implicated in tumor metastasis suppression, was previously demonstrated to be directly associated with menin. Menin has been shown to have a GTPase activity in the presence of nm23 ⁽²⁴⁸⁾. Several disease-causing missense mutants of menin retain similar GTPase activities, but are less stable than the wild-type menin in culture cells. The instability of the pathogenic menin mutants is now being investigated.
    Autosomal dominant hypocalcemia is a hereditary syndrome caused by gain-of-function mutations of the calcium sensing receptor. A novel germline mutation S820F was identified as a causative mutation in a family with this syndrome ⁽²⁴⁹⁾.
Involvement of Orphan Nuclear Receptor in Tumorigenesis

    NOR1 is an orphan nuclear receptor of the steroid hormone receptor superfamily and is induced by various stimuli ^(250,²⁵¹⁾. NOR1 is involved in the development of extraskeletal myxoid chondrosarcoma, in which chromosomal translocation creates a fusion between EWS and NOR1 genes, generating EWS/NOR1 fusion protein. To elucidate the role of EWS/NOR1 in the tumor development, a yeast functional complementation screening method was developed. By use of this new method, EWS/NOR1, but not EWS or NOR1 alone, has been shown to mimic yeast Snu23, a small nuclear ribonucleoprotein that is essential for pre-mRNA splicing ⁽²⁵²⁾. Involvement of EWS/NOR1 in pre-mRNA splicing has also been verified in mammalian cells. These findings indicate that EWS/NOR1 gains a biological function affecting the pre-mRNA splicing. This newly developed screening method is widely applicable to studies of gene function.
Pathogenesis of Cancer Cachexia

    Cancer cachexia is a syndrome characterized by anorexia and severe loss of body weight associated with malignant tumors. Appetite regulation in the central nervous system has been studied by examining the hypothalamic expression of neuropeptides. Although the almost normal regulatory mechanism is likely to be maintained, increase of appetite-stimulating neuropeptides, including neuropeptide Y, in response to weight loss has been shown to be attenuated in a mouse model of cancer cachexia ⁽²⁵³⁾. This insensitivity of the central appetite-regulating system partly explains anorexia and body weight loss in the cancer cachexia syndrome.
Toxic Proteins

    Conformational diseases are defined as disorders that involve a change in size or fluctuation in shape of a constituent protein, with resultant self-association and tissue depositions as amyloid fibrils, Lewy bodies, and nuclear inclusion. Post-translational conformational conversions of nontoxic a-helical/random-coils to b-sheet are presumed to lead to diseases including Alzheimer’s disease, prion diseases, Parkinson’s disease, polyglutamine diseases, and a variety of systemic amyloidoses. Pituitary adenylate cyclase activating polypeptide (PACAP) stimulates neuritogenesis and survival of neuronal cells in the central nervous systems. Amyloid b and prion protein fragment, corresponding to pathological peptides of Alzheimer’s disease and prion diseases, respectively, induce apoptotic cell death in PC12 cells. PACAP rescued PC12 cells from cell death induced by these toxic peptides ^(254,²⁵⁵⁾. This protective effect was mediated through PAC1 receptor by activating both PKA and MAP kinases.




20.TUMOR ENDOCRINOLOGY PROJECT



	The Tumor Endocrinology Project aims at the clarification of the pathophysiology of cancer patients leading to the development of new methods for diagnosis and treatment. Tumor development involving endocrine tissues and receptors, pathogenesis of cancer cachexia, and protection of neuroendocrine cells from toxic proteins are currently studied. Multiple Endocrine Neoplasia Type 1 and Other Heritable Endocrine Diseases Multiple endocrine neoplasia type 1 is a familial cancer syndrome characterized by the simultaneous occurrence of various endocrine tumors. Germline and somatic mutations of the responsible gene MEN1 in patients with this syndrome and related disorders have been analyzed in collaboration with regional hospitals, and revealed novel pathogenic mutations. The molecular function of menin, the protein product of the MEN1 gene, is unknown. Nm23, a protein implicated in tumor metastasis suppression, was previously demonstrated to be directly associated with menin. Menin has been shown to have a GTPase activity in the presence of nm23 ⁽²⁴⁸⁾. Several disease-causing missense mutants of menin retain similar GTPase activities, but are less stable than the wild-type menin in culture cells. The instability of the pathogenic menin mutants is now being investigated. Autosomal dominant hypocalcemia is a hereditary syndrome caused by gain-of-function mutations of the calcium sensing receptor. A novel germline mutation S820F was identified as a causative mutation in a family with this syndrome ⁽²⁴⁹⁾. Involvement of Orphan Nuclear Receptor in Tumorigenesis NOR1 is an orphan nuclear receptor of the steroid hormone receptor superfamily and is induced by various stimuli ^(250,²⁵¹⁾. NOR1 is involved in the development of extraskeletal myxoid chondrosarcoma, in which chromosomal translocation creates a fusion between EWS and NOR1 genes, generating EWS/NOR1 fusion protein. To elucidate the role of EWS/NOR1 in the tumor development, a yeast functional complementation screening method was developed. By use of this new method, EWS/NOR1, but not EWS or NOR1 alone, has been shown to mimic yeast Snu23, a small nuclear ribonucleoprotein that is essential for pre-mRNA splicing ⁽²⁵²⁾. Involvement of EWS/NOR1 in pre-mRNA splicing has also been verified in mammalian cells. These findings indicate that EWS/NOR1 gains a biological function affecting the pre-mRNA splicing. This newly developed screening method is widely applicable to studies of gene function. Pathogenesis of Cancer Cachexia Cancer cachexia is a syndrome characterized by anorexia and severe loss of body weight associated with malignant tumors. Appetite regulation in the central nervous system has been studied by examining the hypothalamic expression of neuropeptides. Although the almost normal regulatory mechanism is likely to be maintained, increase of appetite-stimulating neuropeptides, including neuropeptide Y, in response to weight loss has been shown to be attenuated in a mouse model of cancer cachexia ⁽²⁵³⁾. This insensitivity of the central appetite-regulating system partly explains anorexia and body weight loss in the cancer cachexia syndrome. Toxic Proteins Conformational diseases are defined as disorders that involve a change in size or fluctuation in shape of a constituent protein, with resultant self-association and tissue depositions as amyloid fibrils, Lewy bodies, and nuclear inclusion. Post-translational conformational conversions of nontoxic a-helical/random-coils to b-sheet are presumed to lead to diseases including Alzheimer’s disease, prion diseases, Parkinson’s disease, polyglutamine diseases, and a variety of systemic amyloidoses. Pituitary adenylate cyclase activating polypeptide (PACAP) stimulates neuritogenesis and survival of neuronal cells in the central nervous systems. Amyloid b and prion protein fragment, corresponding to pathological peptides of Alzheimer’s disease and prion diseases, respectively, induce apoptotic cell death in PC12 cells. PACAP rescued PC12 cells from cell death induced by these toxic peptides ^(254,²⁵⁵⁾. This protective effect was mediated through PAC1 receptor by activating both PKA and MAP kinases.