Crosstalk among FLT-3,PTEN,PI3K signaling pathway,Notch, and p53

As PTEN is a suppressor of PI3K-akt signaling pathway, it is easy to find PTEN mutation in tumor cells.In T-ALL, Notch signaling pathway can regulate PTEN (phosphatase and tensin homolog) through HES1 and cMYC. Both HES1 and cMYC are transcriptional activators which are directly controlled by Notch1. They can control the expression of PTEN by binding to the PTEN promoter directly.
And HES1 actually is a negative regulator of the PTEN promoter. The constitutive activation of Notch signaling pathway can result in over-expression of PI3K-AKT signaling because over-activation of Notch signaling pathway can inhibit PTEN and then PI3K-Akt signaling are over-activation as lacking the suppression of PTEN.[7] There is a network interaction among those kinases encoded by mutation genes. In another pathway,over-activation of Notch directly upregulate mTOR independent of PI3K-Akt signaling pathway even mTOR is a downstream target of Akt.[10] Besides that, Notch are also can regulate ARF and MDM2. At last, over-activation Notch result in down-regulation of p53 and induce cancer. Akt would also activate MDM2. P53 would be down-regulated obviously by 3 factors. (1)As PTEN can bind directly to p53 to protect p53 from MDM2′s inhibition, down-regulation of PTEN result in down-regulation of p53. [16](2)Over-activated Akt by low expression of PTEN and over-activation of FLT-3 can phosphorylate MDM2 leading to down-regulation of p53. [15](3) Because of low expression of PTEN, MDM2 would be over-activated as PTEN can inhibit MDM2 so that p53 is down-regulated. [16]Besides that, over-activated FLT-3 contributes to over-activated PI3K-Akt signaling pathway. In conclusion, those different kinases and different mutation are related to each other as a network and work together inducing normal cells to cancer cells.
flt-3 and p53

Figure 3. Crosstalk among different mutation genes in ALL including Notch,PTEN, p53, and PI3K.

Future direction
There are many genetic mutations in ALL. With efforts from researchers, different genetic mutation related to ALL were discovered and sequenced . It is interesting that a lot of genetic mutation involved in ALL encode important kinases which can effect the signaling pathways and play a key role in cell growth, cell proliferation, apoptosis and so on. FLT-3 mutation, p53 mutation ,Notch mutation are all mutation related to kinases. Different patients with different mutation is a big problem. Maybe we should not just focus on one gene mutation. There is a group of mutation genes in ALL.
Maybe,the relationship between genetic mutation and diseases is signal transducion. From signaling pathway, we can collect a group of genes involved in one cellular function. There is another centre rule appear. One way is from genes mutation or genetic disorder to signal pathways over-activation or inhibition. The signaling pathways can interact with each other which means that genetic mutation can influence each other indirectly.
Maybe confirming the ALL patients' mutation genes by sequencing and using a correct group of inhibitors is a good choice for patients to reduce the drugs resistance and improve the drugs' effects.
LY294002, nvp-bez235, high through-out screening

Reference:

[1]Armstrong, S. A., M. E. Mabon, et al. FLT3 mutations in childhood acute lymphoblastic leukemia. Blood, 2004, 103(9): 3544-3546.

[2]Suter, S. E., G. W. Small, et al. FLT3 mutations in canine acute lymphocytic leukemia. BMC Cancer, 2011, 11: 38.

[3]Gutierrez, A., T. Sanda, et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood, 2009, 114(3): 647-650.

[4]Radtke F,Wilson A, Mancini SJ, MacDonald HR.Notch regulation of lymphocyte development and function. Nat Immunol, 2004,5:247-253.

[5]RM Demarest, F Ratti1 and AJ Capobianco. It's T-ALL about Notch. Oncogene, 2008, 27: 5082-5091.

[6]A Larson Gedman, Q Chen, et al. The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia, 2009, 23: 1417–1425.

[7] Palomero, T., M. L. Sulis, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med, 2007, 13(10): 1203-1210.

[8]Palomero, T. et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc. Natl. Acad. Sci, 2006, 103: 18261–18266 .

[9]Weng, A.P. et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev, 2006, 20: 2096–2109.

[10]Chan, S. M., A. P. Weng, et al. Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood, 2007, 110(1): 278-286.

[11]Speck NA, Gillil and DG. Core-binding factors in haematopoiesis and leukaemia.Nat Rev Cancer 2002,2:502-13.

[12]Ching-Hon Pui, Mary V. Relling et al. Acute Lymphoblastic Leukemia. N Engl J Med, 2004, 350:1535-48.

[13]Chow LM, Baker SJ. PTEN function in normaland neoplastic growth. Cancer Lett, 2006, 241:184-196.

[14]FRE´DE´RIQUE LOGEAT et al. The Notch1 receptor is cleaved constitutively by a furin-like convertase, Proc. Natl. Acad. Sci.USA,95:8108–8112.

[15]Ashcroft, M., Ludwig, R., Woods, D. B., Copeland, T. D., Weber, H. O., MacRae,E. J., and Vousden, K. H. Phosphorylation of HDM2 by Akt. Oncogene,2002,21:1955-1962.

[16]Muxiang Zhou, et al.PTEN Reverses MDM2-mediated Chemotherapy Resistance by Interacting with p53 in Acute Lymphoblastic Leukemia Cells.Cancer Res,2003,63:6357-6362.
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