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Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene The journal of Clinical Investigation 112:1809-1820 (2003) Lien Hsu Outlines ► Introduction---- Autophagy Beclin 1 Hypothesis ► Methods and Results ► Discussion ► Critics Introduction----what is autophagy? Autophagy (autonomous phagocytosis) Functions: I. allows cells to survive during starvation II.enables cells to undergo structural remodeling during differentiation and development III.prevents aging ► Defects of autophagy--?--Development of cancer Malignant cells----lower basal autophagic activity ; no increased protein degradation rates Beclin 1 I. promotes starvation-induced autophagy in human breast carcinoma cells II. 17q21, a tumor-susceptibility locus III. Monoallelically deleted----in 40-75% of cases of human sporadic breast, ovarian, and prostate cancer Hypothesis Inference----tumor suppressor? *biallelic mutations of beclin 1 have not been demonstrated in human cancer~~ haplo-insufficient tumor suppressor gene? Methods and Results ► ► Knock-out mice beclin 1 +/+/- x +/- => F1----embryonic lethality of homozygous-deficient mice Beclin 1 heterozygous disruption in mice results in increased spontaneous tumorigenesis Macroscopic malignancy All malignancies +/ +/+ Prevalence of macroscopic malignancies any malignancy lung carcinoma hepatocellular carcinoma Lymphomas (gray) and lymphoproliferative disease (black or white) Lung carcinoma well-differentiated papillary lung carcinoma in beclin 1(+/-) anti-Beclin 1(lung) anti-TTF-1(lung carcinoma): specific transcription factor in bronchial and type II alveolar epithelial cells Hepatocellular carcinoma Gross pathology of liver tumor anti-Beclin 1(hepatocellular carcinoma) inset shows lymphoma adjacent to normal kidney anti-Pax5 (dark purple anti-CD3 (brown): DLCL Lymphoproliferative disease in the thymus Lymphomas anti-BCL-6: transcriptional repressor controls germinal center formation: human B cell lymphoma Southern blot to detect wt and disrupted beclin 1 allele in tumor and normal tissuse *no deletion or rearrangement of remaining wt beclin 1 allele Results suggest: ► functional inactivation of one beclin 1 is sufficient to promote tumorigenesis ► beclin gene 1 is a haplo-insufficient tumor-suppressor Beclin 1 heterozygous disruption in mice “accelerates” the development of HBV (hepatisis B virus)-induced premalignant lesions The model---I. Cross beclin +/- X beclin +/+ with HBV transgenesis (13m) II.liver is a major site of nutrient starvation-induced autophagy preneoplastic small-cell dysplasia in the liver Extent of small-cell dysplasia in liver HBV transgenic mice (13m) (beclin 1+/- express HBV) +/+ HBV trangenic mice(white) +/- HBV transgenic mice(black) Results suggest: ► Beclin 1 heterozygous disruption in mice accelerates the development of HBVinduced premalignant lesions Beclin 1 heterozygous disruption results in increased cellular proliferation in vivo intraepithelial Epithelial duct beclin 1 heterozygous deficiency results in abnormal cellular proliferation in the TEBs and mammary ducts. Studies for proproliferation affects in germinal center formation: B lymphocyte neoplasia adenomyoepithelioma acinar neoplasia Terminal end bud TEB Mammary ducts Number Size Result suggest: ► beclin 1 heterozygous disruption increases cellular proliferation in vivo, beginning at an early age. Inference: the increased cellular proliferation in beclin 1+/– mice may increase the number of genetic mutations that occur over the lifetime of the animals, thereby contributing to the increased spontaneous tumorigenesis that occurs in older beclin 1+/– mice Q: whether beclin 1 +/- affects its known function in autophagy? Beclin 1 heterozygous disruption decrases autophagy in vivo GFP-LC3 marker---Upon stimulation of autophagy, LC3 localizes to preautophagosomal membranes * The muscle has been shown to be an important site of starvation-induced autophagy 2m old 24hr starvation Q: whether beclin 1 heterozygous deletion affects autophagy in any of the tissues associated with increased spontaneous tumorigenesis? ► Lymphocyte---no; liver---variably expressed; lung----typeII aveolar and bronchial epithelial cells ► Well-differentiated papillary lung carcinoma----show in bronchial cell origin Results suggest---► beclin 1 heterozygous deletion reduces autophagic activity in a tissue that undergoes starvation-induced increases in autophagy (i.e. muscle) Discussion ► Autophagy genes may represent a novel class of tumorsuppressor genes. ► The precise mechanisms by which the autophagy fuction of Beclin 1 contributes to tumor suppression is not known. ► Autophagy may also contribute to tumor suppression by degrading specific cellular organelles and long-lived proteins that are essential for regulating cell growth, thereby functioning as a brake on cell growth in response to mitogenic signals. Critics ► No normal histologic slides to compare. ► Why didn’t the authors mention if expression of Beclin 1 decreases in all neoplastic lesions or not? ► Is there any other possible autophagy-related gene involved in tumorigenesis? ► Is tumorigenesis really through any funtion of autophagy? or just because of beclin 1?