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Molecular Mechanisms of Cancer

Genetic instability drives tumor progression by generating mutations in oncogenes and tumor suppressor genes. Major signaling pathways involved in inter- and intra-cellular communication leading to malignant phenotypes include GPCR signaling, Ras/integrin signaling, Akt signaling, TGF-β/BMP signaling, WNT signaling, Notch and Hedgehog (Hh) signaling, and Death receptor signaling.In the WNT pathway, WNT binds to the receptor Fzd and LRP5/6. This leads to the activation of Dsh and inhibits GSK3β function. Ctnn-β translocates to the nucleus to signal as a heterodimer with LEF/TCF proteins...

Molecular Mechanisms of Cancer

Pathway Summary

Genetic instability drives tumor progression by generating mutations in oncogenes and tumor suppressor genes. Major signaling pathways involved in inter- and intra-cellular communication leading to malignant phenotypes include GPCR signaling, Ras/integrin signaling, Akt signaling, TGF-β/BMP signaling, WNT signaling, Notch and Hedgehog (Hh) signaling, and Death receptor signaling.In the WNT pathway, WNT binds to the receptor Fzd and LRP5/6. This leads to the activation of Dsh and inhibits GSK3β function. Ctnn-β translocates to the nucleus to signal as a heterodimer with LEF/TCF proteins. Hh signaling genes have overlapping functions with WNT signaling. Hh signaling pathway comprises the Hh ligand, a receptor circuit composed of Ptc, Smo and a cytoplasmic complex that regulates the Gli transcriptional effectors. In the absence of ligand, Ptc inhibits Smo, and Gli acts as a transcriptional repressor. When Hh binds Ptc, Gli enters the nucleus via a complex of Gli, Fused and SuFu, where it is involved in the transcription of Hh target genes. Dsh directly modulates Notch signaling. The Notch COOH-terminal fragment NEXT is cleaved by γ-secretase and TACE to release NICD, which translocates to the nucleus and associates with RBPJ-κ, p300, HAT1 and HIF1α and activates expression of target genes.The TGF-β superfamily is divided into two general branches; the TGF/Activin/Nodal and BMP/GDF branches. These branches propagate signals by phosphorylating the SMAD family of intracellular mediators. Phosphorylated SMADs translocate to the nucleus and associate with p107, E2Fs, MIZ1, Myc and MAX. TGF-β negatively regulates WNT signaling by inhibiting LEF1/TCF2-3 function. The growth inhibitory effects of TGF-β are mediated through the induction of CKIs like p15(INK4B), p21(CIP1), p27(KIP1) and down regulation of CDKs and cyclins like CcnD, CcnE, CcnA, CDK2, CDK4 and CDK6. Other CKIs like p16(INK4A), p18(INK4C), p19(INK4D) and viral oncoprotein HPV-E7 maintain the Rb protein in hypophosphorylated state, preventing E2F from inducing the expression of genes required for G1-S phase transition.p16(INK4A) inhibits CDK4/6 and CcnD whereas p14(ARF) interacts with MDM2 to block degradation of p53. DNA damage activates ATM and ATR, DNA-PK and HIPK. Phosphorylation by ATM/ATR through Chk1/Chk2 leads to p53 stabilization and activation. Chk1/2 activates CDC25, which activates CDK2/CcnE and CDK4/CDK6/CcnD to promote progression through S phase while CDC25B/C activates CDC2/CcnB and promotes progression into mitosis. Aberrant expression of CKIs, CDKs and cyclins leads to establishment of a variety of cancers.GPCR signaling activates Ras via G-protein, PLC-β, PIP3 or DAG, CamK2/PKC and RasGRF/RasGRP. Further, Ras, c-Raf, MEK1/2-MP1-ERK1/2 activates c-Jun/c-Fos to regulate cyclin expression. Ras activates Akt signaling through PI3K/PIP3 activation.Cytokine receptors recruit SHP2, GRB2, SOS, Ras, SHC and JAKs to activate PI3K, whereas growth factors and RTKs recruit GAB1/2, Cbl and IRS1 to activate PI3K. PI3Ks indirectly activates Akt, which controls mitochondrial and Fas/FasL mediated apoptosis. Fas binds to FasL and interacts with FADD, TRADD and ASK1 to recruit caspase8 and 10. Caspase8 and 10 activate caspase3, 6 and 7. Caspase8 cleaves BID, to form tBID, which enters the mitochondria where it facilitates MMP through BAX and BAK activation along with BIM. MMP triggers the release of CytoC and SMAC. CytoC binds to APAF1/caspase9, which activates caspase3. Caspase8 also cleaves procaspase3, 6 and 7 directly and activates it, which leads to apoptosis. The elucidation of the molecular mechanisms by which normal cells transduce proliferative signals or make life or death decisions provides an opportunity to search for novel molecular targets for pharmacologic intervention in cancer.

Molecular Mechanisms of Cancer Genes list

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