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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.
165:, 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.
115:, 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
111:, 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
98:, 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.
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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,
182:(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.
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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
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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
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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
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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
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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.
409:
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 "
477:
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
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222:, 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
486:
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
428:
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
602:"Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes"
847:
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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".
889:
729:
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Leung et al. "Vascular
Endothelial Growth Factor is a Secreted Angiogenic Mitogen". 8 December 1989, Science, Vol. 246, pp 1306-1309.
555:"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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330:-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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to be passed. One of the most important of these is
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360:(MAPK) pathways can induce enzymes such as the
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498:Basic Immunology and its Medical Application
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345:and, therefore, cannot undergo mitosis.
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230:. Mitogens are often used to stimulate
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957:Extracellular signal-regulated kinases
600:Font-Nieves, M; Sans-Fons, MG (2012).
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358:Mitogen-activated protein kinase
60:mitogen-activated protein kinase
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606:Journal of Biological Chemistry
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1226:Myelin-associated glycoprotein
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117:platelet derived growth factor
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571:10.1016/s0165-2478(99)00068-1
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42:that induces a cell to begin
1292:N-Acetylglucosamine receptor
62:(MAPK), leading to mitosis.
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1142:Asialoglycoprotein receptor
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186:Multiple mutations required
173:Resistance to anti-mitogens
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531:10.1007/3-540-27806-0_1183
180:transforming growth factor
140:Independence from mitogens
131:Mitogens are important in
27:Type of protein or peptide
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770:MAP kinase kinase kinases
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974:C-Jun N-terminal kinases
761:MAP kinase kinase kinase
702:Medical Subject Headings
665:10.1177/1933719107309647
619:10.1074/jbc.M111.327874
121:epidermal growth factor
496:Barret, James (1980).
324:gram-negative bacteria
127:Relationship to cancer
94:pathway, downregulate
34:is a small bioactive
1382:Cell cycle regulators
1157:Mannan-binding lectin
738:MAP kinase activation
653:Reproductive Sciences
1344:Phytohaemagglutinin
260:phytohaemagglutinin
102:Endogenous mitogens
58:pathways involving
56:signal transduction
559:Immunology Letters
317:Lipopolysaccharide
288:lipopolysaccharide
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900:MAP kinase kinase
540:978-3-540-27806-1
507:978-0-8016-0495-9
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195:Use in immunology
150:positive feedback
82:" and depends on
80:restriction point
16:(Redirected from
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1164:Mannose receptor
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1317:Toxalbumins
1066:Phosphatase
1023:ERK5 kinase
335:specificity
232:lymphocytes
220:lymphokines
200:Lymphocytes
119:(PDGF) and
52:Mitogenesis
18:Mitogenesis
1397:Immunology
1376:Categories
949:MAP kinase
744:Initiation
397:References
353:Other uses
250:Acts upon
243:Acts upon
228:antibodies
72:cell cycle
1152:Collectin
579:0165-2478
332:antigenic
154:oncogenes
109:zebrafish
96:cyclin D1
1334:Mitogens
1297:Selectin
1287:Galectin
1277:Calnexin
1261:SIGLEC12
1256:SIGLEC10
1191:Neurocan
1186:Brevican
1181:Versican
1176:Aggrecan
698:Mitogens
681:10706385
673:18212353
638:22219191
587:10482357
410:101-111.
375:See also
123:(EGF).
1387:Mitosis
1251:SIGLEC9
1246:SIGLEC8
1241:SIGLEC7
1236:SIGLEC6
1231:SIGLEC5
1119:lectins
1115:Protein
873:MAP3K11
868:MAP3K10
858:MAP3K13
853:MAP3K12
751:Mitogen
629:3307308
391:Lectins
252:B cells
245:T cells
216:T cells
208:antigen
204:B cells
84:cyclins
48:mitosis
40:peptide
36:protein
32:mitogen
1361:BanLec
1203:SIGLEC
1126:Animal
1050:MAPK15
1016:MAPK14
1011:MAPK13
1006:MAPK12
1001:MAPK11
989:MAPK10
939:MAP2K7
934:MAP2K6
929:MAP2K5
924:MAP2K4
919:MAP2K3
914:MAP2K2
909:MAP2K1
878:MAP3K7
863:MAP3K9
810:MAP3K8
805:MAP3K7
800:MAP3K6
795:MAP3K5
790:MAP3K4
785:MAP3K3
780:MAP3K2
775:MAP3K1
704:(MeSH)
679:
671:
636:
626:
585:
577:
537:
504:
365:enzyme
328:thymus
276:(conA)
133:cancer
74:. The
1327:Ricin
1322:Abrin
1310:Plant
1270:Other
1147:KLRD1
1045:MAPK6
1040:MAPK4
1028:MAPK7
984:MAPK9
979:MAPK8
967:MAPK3
962:MAPK1
816:RAFs
677:S2CID
369:PTGS2
362:COX-2
322:from
320:toxin
304:(PWM)
290:(LPS)
262:(PHA)
226:, or
1221:CD33
1216:CD22
890:CDC7
848:MLKs
840:KSR2
835:KSR1
830:BRAF
825:ARAF
820:RAF1
669:PMID
634:PMID
583:PMID
575:ISSN
535:ISBN
502:ISBN
310:yes
296:yes
240:Name
163:HER2
88:TP53
50:).
1055:NLK
883:ZAK
661:doi
624:PMC
614:doi
610:287
567:doi
527:doi
326:is
307:yes
282:no
279:yes
268:no
265:yes
92:Ras
38:or
1378::
1117::
675:.
667:.
657:15
655:.
632:.
622:.
608:.
604:.
581:.
573:.
563:69
561:.
557:.
533:,
444:^
371:.
337:.
293:no
254:?
214:.
30:A
1107:e
1100:t
1093:v
842:)
731:e
724:t
717:v
683:.
663::
640:.
616::
589:.
569::
529::
510:.
247:?
20:)
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