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inactivates the tumor suppressor pRb is far more tumorigenic than either protein alone. Tumor cells are also resistant to the hyperproliferation stress response. Normal cells have apoptotic proteins that will respond to an overstimulation of mitogenic signaling pathways by triggering cell death or senescence. This generally prevents the onset of cancer from a single oncogenic mutation. In tumor cells, there is generally another mutation that inhibits apoptotic proteins as well, suppressing the hyperproliferation stress response.
154:, a receptor tyrosine kinase that responds to the mitogen EGF. Overexpression of HER2 is common in 15-30% of breast cancers, allowing the cell cycle to progress even with extremely low concentrations of EGF. The overexpression of kinase activity in these cells aids in their proliferation. These are known as hormone-dependent breast cancers, as the kinase activation in these cancers is connected to exposure to both growth factors and estradiol.
104:, such as vascular endothelial growth factor, are also capable of directly acting as mitogens, causing growth by directly inducing cell replication. This is not true for all growth factors, as some growth factors instead appear to cause mitogenic effects like growth indirectly by triggering other mitogens to be released, as evidenced by their lack of mitogenic activity in vitro, which VEGF has. Other well-known mitogenic growth factors include
100:, an endogenous mitogen Nrg1 is produced in response to indications of heart damage. When it is expressed, it causes the outer layers of the heart to respond by increasing division rates and producing new layers of heart muscle cells to replace the damaged ones. This pathway can potentially be deleterious, however: expressing Nrg1 in the absence of heart damage causes uncontrolled growth of heart cells, creating an enlarged heart. Some
87:, a cyclin-dependent kinase, if they are not stimulated by the presence of mitogens. In the presence of mitogens, sufficient cyclin D1 can be produced. This process cascades onwards, producing other cyclins which stimulate the cell sufficiently to allow cell division. While animals produce internal signals that can drive the cell cycle forward, external mitogens can cause it to progress without these signals.
167:
anti-mitogens allow the cell cycle to move forward when it should be prevented by some anti-mitogenic mechanism. This resistance to anti-mitogens might simply arise from overstimulation by positive mitogens. In other cases, tumor cells possess loss-of-function mutations in some part of the anti-mitogenic pathway. For example, consider the well-known anti-mitogen,
171:(TGF-π±). TGF-π± works by binding to cell-surface receptors and activating the Smad gene regulatory proteins. Smad proteins then trigger an increase in p15, which inhibits cyclin D1 and prevents cell cycle progression. In many cancers, there is a loss-of-function mutation in the Smad proteins, thus negating the entire anti-mitogenic pathway.
179:
Not just one but multiple mitogenic mutations are required for cancer to proliferate. Generally, multiple mutations in different subsystems (an oncogene and a tumor suppressor gene) are the most effective at causing cancer. For example, a mutation that hyperactivates the oncogene Ras and another that
145:
to be identified, p28sis from the simian sarcoma virus, which causes tumorigenesis in the host animal. Scientists found that p28sis has a nearly identical amino acid sequence as human platelet-derived growth factor (PDGF). Thus, tumors formed by the simian sarcoma virus are no longer dependent on the
157:
Third, downstream effectors of mitogenic signaling are often mutated in cancer cells. An important mitogenic signaling pathway in humans is the Ras-Raf-MAPK pathway. Mitogenic signaling normally activates Ras, a GTPase, that then activates the rest of the MAPK pathway, ultimately expressing proteins
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Second, cancer cells can have mutated cell-surface receptors for mitogens. The protein kinase domain found on mitogenic receptors is often hyperactivated in cancer cells, remaining turned on even in the absence of external mitogens. Additionally, some cancers are associated with an overproduction of
166:
Cell proliferation is often regulated by not only external mitogens but also by anti-mitogens, which inhibit cell cycle progression past G1. In normal cells, anti-mitogenic signaling as a result of DNA damage, preventing the cells from replicating and dividing. Tumor cells that are resistant to
124:
research due to their effects on the cell cycle. Cancer is in part defined by a lack of, or failure of, control in the cell cycle. This is usually a combination of two abnormalities: first, cancer cells lose their dependence on mitogens. Second, cancer cells are resistant to anti-mitogens.
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that stimulate cell cycle progression. It is likely that most, if not all, cancers have some mutation in the Ras-Raf-MAPK pathway, most commonly in Ras. These mutations allow the pathway to be constitutively activated, regardless of the presence of mitogens.
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Rather than requiring endogenous or external mitogens to continue the cell cycle, cancer cells are able to grow, survive, and replicate without mitogens. Cancer cells may lose their dependence on external mitogens by a variety of pathways.
398:
Bohmer et al. "Cytoskeletal
Integrity Is Required throughout the Mitogen Stimulation Phase of the Cell Cycle and Mediates the Anchorage-dependent Expression of Cyclin DI". January 1996, Molecular Biology of the Cell, Vol. 7, pp.
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Waterfield, M., Scrace, G., Whittle, N. et al. Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature 304, 35β39 (1983) doi:10.1038/304035a0
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fluctuations of PDGF that control cell growth; instead, they can produce their own mitogens in the form of p28sis. With enough p28sis activity, the cells can proliferate without restriction, resulting in cancer.
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Mitogens can be either endogenous or exogenous factors. Endogenous mitogens function to control cell division is a normal and necessary part of the life cycle of multicellular organisms. For example, in
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can proliferate to produce more memory cells or plasma B cells. This is how the mitogen works, that is, by inducing mitosis in memory B cells to cause them to divide, with some becoming plasma cells.
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is controlled most directly by mitogens: further cell cycle progression does not need mitogens to continue. The point where mitogens are no longer needed to move the cell cycle forward is called the "
466:
Mitri Z, Constantine T, O'Regan R (2012). "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New
Advances in Therapy". Chemotherapy Research and Practice. 2012: 743193
543:
211:, which are substances that modify the host organism to improve its immunity. B cells, on the other hand, divide to produce plasma cells when stimulated by mitogens, which then produce
475:
Santen et al. "The role of mitogen-activated protein (MAP) kinase in breast cancer". February 2002, The
Journal of Steroid Biochemistry and Molecular Biology, Vol. 80, pp. 239-256
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loop - tumor cells produce their own mitogens, which stimulate more tumor cells to replicate, which can then produce even more mitogens. For example, consider one of the earliest
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Gemberling et al. "Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish". 1 April 2015, eLifeSciences.
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Foijer et al. "Mitogen requirement for cell cycle progression in the absence of pocket protein activity". December 2005, Cancer Cell, Vol. 8, pp. 455-466
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mitogenic receptors on the cell surface. With this mutation, cells are stimulated to divide by abnormally low levels of mitogens. One such example is
591:"Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes"
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Casciani, V; Marinoni, E (2008). "Opposite effect of phorbol ester PMA on PTGS2 and PGDH mRNA expression in human chorion trophoblast cells".
878:
718:
428:
Leung et al. "Vascular
Endothelial Growth Factor is a Secreted Angiogenic Mitogen". 8 December 1989, Science, Vol. 246, pp 1306-1309.
544:"Bacterial lipopolysaccharide induced B cell activation is mediated via a phosphatidylinositol 3-kinase dependent signaling pathway"
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is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a mitogen is that it triggers
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undergo mitosis when stimulated by mitogens to produce small lymphocytes that are then responsible for the production of
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Mitogens act primarily by influencing a set of proteins which are involved in the restriction of progression through the
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First, cancer cells can produce their own mitogens, a term called autocrine stimulation. This can result in a deadly
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319:-independent. They may directly activate B cells through the PI3-kinase signalling pathway, regardless of their
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Assenmacher, Mario; Avraham, Hava
Karsenty; Avraham, Shalom; Bala, Shukal, eds. (2005), "Pokeweed Mitogen",
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and thereby assess immune function. The most commonly used mitogens in clinical laboratory medicine are:
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Morgan, David (2007). βThe Cell Cycle: Principles of
Controlβ. New Science Press.
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can enter mitosis when they are activated by mitogens or antigens.
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Venkataraman, C.; Shankar, G.; Sen, G.; Bondada, S. (1999-08-03).
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349:(MAPK) pathways can induce enzymes such as the
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512:Encyclopedic Reference of Immunotoxicology
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219:. Mitogens are often used to stimulate
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946:Extracellular signal-regulated kinases
589:Font-Nieves, M; Sans-Fons, MG (2012).
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35:, or enhances the rate of division (
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347:Mitogen-activated protein kinase
49:mitogen-activated protein kinase
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595:Journal of Biological Chemistry
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1215:Myelin-associated glycoprotein
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106:platelet derived growth factor
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560:10.1016/s0165-2478(99)00068-1
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31:that induces a cell to begin
1281:N-Acetylglucosamine receptor
51:(MAPK), leading to mitosis.
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1131:Asialoglycoprotein receptor
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175:Multiple mutations required
162:Resistance to anti-mitogens
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520:10.1007/3-540-27806-0_1183
169:transforming growth factor
129:Independence from mitogens
120:Mitogens are important in
16:Type of protein or peptide
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759:MAP kinase kinase kinases
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963:C-Jun N-terminal kinases
750:MAP kinase kinase kinase
691:Medical Subject Headings
654:10.1177/1933719107309647
608:10.1074/jbc.M111.327874
110:epidermal growth factor
485:Barret, James (1980).
313:gram-negative bacteria
116:Relationship to cancer
83:pathway, downregulate
23:is a small bioactive
1371:Cell cycle regulators
1146:Mannan-binding lectin
727:MAP kinase activation
642:Reproductive Sciences
1333:Phytohaemagglutinin
249:phytohaemagglutinin
91:Endogenous mitogens
47:pathways involving
45:signal transduction
548:Immunology Letters
306:Lipopolysaccharide
277:lipopolysaccharide
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889:MAP kinase kinase
529:978-3-540-27806-1
496:978-0-8016-0495-9
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184:Use in immunology
139:positive feedback
71:" and depends on
69:restriction point
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1306:Toxalbumins
1055:Phosphatase
1012:ERK5 kinase
324:specificity
221:lymphocytes
209:lymphokines
189:Lymphocytes
108:(PDGF) and
41:Mitogenesis
1386:Immunology
1365:Categories
938:MAP kinase
733:Initiation
386:References
342:Other uses
239:Acts upon
232:Acts upon
217:antibodies
61:cell cycle
1141:Collectin
568:0165-2478
321:antigenic
143:oncogenes
98:zebrafish
85:cyclin D1
1323:Mitogens
1286:Selectin
1276:Galectin
1266:Calnexin
1250:SIGLEC12
1245:SIGLEC10
1180:Neurocan
1175:Brevican
1170:Versican
1165:Aggrecan
687:Mitogens
670:10706385
662:18212353
627:22219191
576:10482357
399:101-111.
364:See also
112:(EGF).
1376:Mitosis
1240:SIGLEC9
1235:SIGLEC8
1230:SIGLEC7
1225:SIGLEC6
1220:SIGLEC5
1108:lectins
1104:Protein
862:MAP3K11
857:MAP3K10
847:MAP3K13
842:MAP3K12
740:Mitogen
618:3307308
380:Lectins
241:B cells
234:T cells
205:T cells
197:antigen
193:B cells
73:cyclins
37:mitosis
29:peptide
25:protein
21:mitogen
1350:BanLec
1192:SIGLEC
1115:Animal
1039:MAPK15
1005:MAPK14
1000:MAPK13
995:MAPK12
990:MAPK11
978:MAPK10
928:MAP2K7
923:MAP2K6
918:MAP2K5
913:MAP2K4
908:MAP2K3
903:MAP2K2
898:MAP2K1
867:MAP3K7
852:MAP3K9
799:MAP3K8
794:MAP3K7
789:MAP3K6
784:MAP3K5
779:MAP3K4
774:MAP3K3
769:MAP3K2
764:MAP3K1
693:(MeSH)
668:
660:
625:
615:
574:
566:
526:
493:
354:enzyme
317:thymus
265:(conA)
122:cancer
63:. The
1316:Ricin
1311:Abrin
1299:Plant
1259:Other
1136:KLRD1
1034:MAPK6
1029:MAPK4
1017:MAPK7
973:MAPK9
968:MAPK8
956:MAPK3
951:MAPK1
805:RAFs
666:S2CID
358:PTGS2
351:COX-2
311:from
309:toxin
293:(PWM)
279:(LPS)
251:(PHA)
215:, or
1210:CD33
1205:CD22
879:CDC7
837:MLKs
829:KSR2
824:KSR1
819:BRAF
814:ARAF
809:RAF1
658:PMID
623:PMID
572:PMID
564:ISSN
524:ISBN
491:ISBN
299:yes
285:yes
229:Name
152:HER2
77:TP53
39:).
1044:NLK
872:ZAK
650:doi
613:PMC
603:doi
599:287
556:doi
516:doi
315:is
296:yes
271:no
268:yes
257:no
254:yes
81:Ras
27:or
1367::
1106::
664:.
656:.
646:15
644:.
621:.
611:.
597:.
593:.
570:.
562:.
552:69
550:.
546:.
522:,
433:^
360:.
326:.
282:no
243:?
203:.
19:A
1096:e
1089:t
1082:v
831:)
720:e
713:t
706:v
672:.
652::
629:.
605::
578:.
558::
518::
499:.
236:?
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