MST1 gene and prostate cancer. Professor:Dr.Gheibi Supplier:Fariba Karimiyan 1 5/10/1394
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1 MST1 gene and prostate cancer Professor:Dr.Gheibi Supplier:Fariba Karimiyan 1
2 contents MST1 gene introduction Classification MST1 activation The role of MST1 in apoptosis The role of MST1 in hemoestasis,wound healing and cancer Hippo signaling Prostate cancer Signs and symotoms PSA level Diagnosis Treatment Future aspects 2 Presented by Fariba Karimian - Dec 2015
3 MST1 gene(1) A protein kinase of the STE20 family. Alternative names: Serin Threonin Kinase 4 ; STK4 Kinase Responsuve To Stress 2; KRS2 MST1(STK4), MST2(STK3) MST kinases subgroups MST3(STK24), MST4(STK26),YSK(STK25) 3 Presented by Fariba Karimian - Dec 2015
4 MST1gene(1) Chromosomal Location : 20q11.2-q13.2 Disease: T-cell Immunodeficiency, Recurrent Infections, And Autoimmunity with or without Cardiac Malformations (TIIAC) caused by mutations affecting the gene 4 Presented by Fariba Karimian - Dec 2015
5 Classification(2) 5 MST kinase family Presented by Fariba Karimian - Dec 2015
6 MST1 kinases Emerging as key signaling molecules that influence: cell proliferation, organ size, cell migration, and cell polarity Studies in this field are focuse on: regulation and function of these kinases in normal physiology and pathologies, including cancer, endothelial malformations, and autoimmune disease(2) 6 Presented by Fariba Karimian - Dec 2015
7 MST1 activation Apoptotic signals as well as other stress signals Both phosphorilation and caspase-mediated cleavage Dimerization 7 Presented by Fariba Karimian - Dec 2015
8 Schematic representation of MST1 kinase. Two residues (Thr183 and Thr187) within the MST1 activation loop are essential for kinase activation(3) 8 Presented by Fariba Karimian - Dec 2015
9 MST1 activation through Raassf and simultaneous removal of negative regulation by Raf-1(2) 9 Presented by Fariba Karimian - Dec 2015
10 The role of MST1 in apoptosis(4) 10 Presented by Fariba Karimian - Dec 2015
11 The role of MST1 in hemoestasis,wound healing and cancer(2) 11 Presented by Fariba Karimian - Dec 2015
12 Hippo signaling components(5) Amphiregulin BIRC5 ciap1 CTGF Cyclin D1 Galpha s Galpha 12/13 Lats1/2 Mob1 Mst1/2 Rho A Sav1 TEADs Yap/Taz 12 Presented by Fariba Karimian - Dec 2015
13 Hippo signaling pathway(6) 13 Presented by Fariba Karimian - Dec 2015
14 Hippo signaling regulation(7) The Hippo pathway mediates the reciprocal regulation of cell proliferation by contact inhibition and mitogenic signaling 14 Presented by Fariba Karimian - Dec 2015
15 MST1 and cancer In order to importance affects of MST1/Lats signaling pathway on cell proliferation,it seems that these kinases has an important role in cancers pathology 15 Presented by Fariba Karimian - Dec 2015
16 MST1 and cancer Hippo-Lats-Yorkie signaling regulates tissue overgrowth and tumorigenesis indrosophila. Mst1 and Mst2 protein kinases;the mammalian Hippo orthologs. Mst1/2 inhibition of Yap1 is an important pathway for tumor suppression in human HCC.(9) 16 Presented by Fariba Karimian - Dec 2015
17 MST1 and pathologeis Loss of MST1 made mouse susceptible to autoimmune diseases including skin lesions around eyes along with enlarged spleen The occurance of the SNPs on MST1 are related to Crohn disease and colitis(10) 17 Presented by Fariba Karimian - Dec 2015
18 Prostate Cancer Prostate cancer has become a major public health problem in Western industrialized countries. Most prostate cancers are very slow growing, but some can grow and spread quickly If the cancer is discovered before it spreads beyond the prostate gland it is potentially curable Prostate cancer is usually found during a routine physical examination (11) 18 Presented by Fariba Karimian - Dec 2015
19 Signs & symptoms(11) In the early stages, there may be no symptoms As men age, the prostate can become enlarged for a number of reasons These symptoms don t mean that cancer is present: starting or stopping urination is a problem slow stream painful urination or ejaculation dribbling frequent urination loss of urinary control blood in urine or ejaculate night-time voiding In advanced cases of prostate cancer, symptoms can include: 1. Weight lose 2. Fatigue 3. Backache or sciatica-like pain, or swelling of the legs that doesn t go away 19 Presented by Fariba Karimian - Dec 2015
20 Cancer 20 Presented by Fariba Karimian - Dec 2015
21 PSA level(12) Many cases today are detected by PSA levels in the 2.5±10 ng/ml range and are confirmed by histology of biopsies Typically, tumours were advanced and extended beyond the organ capsule or had metastasized. In such cases, PSA levels are much higher than 10 ng/ml. 21 Presented by Fariba Karimian - Dec 2015
22 Bone metastases in advanced prostate cancer diagram of sites often affected. 22 Presented by Fariba Karimian - Dec 2015
23 Diagnosis(13) Nowadays, an increasing number of prostate cancers are detected through elevated serum PSA levels. Before PSA assays became routine, many cases were recognized by digital rectal examination (DRE). 23 Presented by Fariba Karimian - Dec 2015
24 Diagnosis Digital rectal examination (DRE) PSA blood test measures the levels of prostate specific antigen. Tissue biopsy Bone Scan,MRI,CT TRUS TURP 24 Presented by Fariba Karimian - Dec 2015
25 Treatment(14) To aid in treatment decisions, nomograms have been introduced, which combine information from digital rectal examination, biopsy histology PSA assays 25 Presented by Fariba Karimian - Dec 2015
26 Future aspects We are intrested in finding the relevance between this cancer and reduced level of MST1 gene expression to might be achieving this gene as biomarker for early detection of prostate cancer in future researches 26 Presented by Fariba Karimian - Dec 2015
27 REFRENCES 1. O'Neill EE, Matallanas D, Kolch W. Mammalian Sterile 20 Like Kinases in Tumor Suppression: An Emerging Pathway. Cancer research. 2005;65(13): Thompson BJ, Sahai E. MST kinases in development and disease. The Journal of cell biology. 2015;210(6): Glantschnig H, Rodan GA, Reszka AA. Mapping of MST1 Kinase Sites of Phosphorylation ACTIVATION AND AUTOPHOSPHORYLATION. Journal of Biological Chemistry. 2002;277(45): Huang J, Wu S, Barrera J, Matthews K, Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell. 2005;122(3): Pan D. The hippo signaling pathway in development and cancer. Developmental cell. 2010;19(4): Pan D. Hippo signaling in organ size control. Genes & development. 2007;21(8): Presented by Fariba Karimian - Dec 2015
28 REFRNCES 9. Zhou D, Conrad C, Xia F, Park J-S, Payer B, Yin Y, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer cell. 2009;16(5): Waterman M, Xu W, Stempak JM, Milgrom R, Bernstein CN, Griffiths AM, et al. Distinct and overlapping genetic loci in Crohn's disease and ulcerative colitis: correlations with pathogenesis. Inflammatory bowel diseases. 2011;17(9): Plata BA, Concepcion MT. Prostate cancer epidemiology. Archivos espanoles de urologia. 2014;67(5): Partin A, Yoo J, Carter HB, Pearson J, Chan D, Epstein J, et al. The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. The Journal of urology. 1993;150(1): Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: Journal of the National Cancer Institute. 2009;101(19): Lardy HA, Marwah P, Marwah A. Prostate cancer treatment. Google Patents; Presented by Fariba Karimian - Dec 2015
29 29 Presented by Fariba Karimian - Dec 2015
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