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Cancer

Carcinogenesis and Neoplasia ... a Companion Site.

Cancer

Cancers arise when cells escape normal controls on cellular proliferation. Cancer is not a single disease, rather the term encompasses a group of conditions that share the characteristic process of uncontrolled cellular proliferation of cells that are typicallly capable of local infiltration into other tissues (invasion). This propensity for invasion and migration is associated with the capacity to metastasize to sites distant from the point of origin. Benign tumors evidence as local overgrowth, but fortunately have minimal or no propensity for tissue infiltration and metastasis. Cancers originating in the same tissue/organ can vary considerably in degree of undifferentiation, sensitivity to chemotherapeutic agents, growth rate, invasiveness, and metastatic potential.

Alteration of a gene that normally controls cell growth can promote the uncontrolled growth characteristic of cancer. The normal forms of dominant genes that function in the various signal transduction cascades that regulate cell growth, proliferation and differentiation are termed proto-oncogenes, and the malignantly transformed genes are termed oncogenes.

For example, mutation in a proto-oncogene, such as a gene which encodes an intracellular signaling protein that is normally activated only by extracellular growth factors, converts the proto-oncogene into an oncogene. The malignantly transformed oncogene encodes an altered form of the signaling protein that now behaves as though activated even in the absence of growth factor binding. The malignant cell line has escaped normal gene regulation and cell cycle control mechanisms and exhibits unchecked proliferation.

A propensity for invasion and metastasis is a critical feature that distinguishes malignancies from benign tumors.

There are many excellent sites with information for those affected by cancer, so the purpose of this site, in conjunction with the companion sites, is an exploration of the cell and molecular biology of malignancy.

synonyms : cancer, tumor, malignancy, neoplasm; cancerous, tumorous, malignant, neoplastic; cancer, neoplasia, oncology.

¤¤ adenoviruses ¤ amplification ¤ carcinogenesis ¤ c-Fos ¤ c-Jun ¤ c-Myc ¤ c-Sis ¤ estrogen receptors ¤ gene amplification ¤ genetic predispositon ¤ HBV ¤ HIV ¤ HPV ¤ HTLV-I ¤ immune evasion ¤ irradiation ¤ malignant transformation ¤ metastasis ¤ mitogens ¤ mutagens ¤ MYC ¤ mutations ¤ neoplasia ¤ neoplastic mutations ¤ NF-κB ¤ non-mutagenic carcinogens ¤ oncogenes ¤ p53 ¤ proliferation ¤ proto-oncogenes ¤ radiation ¤ Ras ¤ Rb ¤ retroviral mechanisms of carcinogenesis ¤ retroviruses ¤ signaling molecules ¤ SRC genes ¤ T-antigens ¤ TP53 ¤ tumor antigens ¤ tumor suppressors ¤ tumorigenic viruses ¤ viral carcinogens ¤ v-Fos ¤ v-Sis ¤ v-Myc ¤

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posted 12/31/2022 at 12/31/2022 11:59:00 PM

carcinogenesis

Carcinogenesis involves damage-induced genetic alterations (mutations) that produce cancers. Mutagenesis causes genetic alterations that may, or may not, result in cancer.
Tables  Malignant Transformation  Oncogenes Proto-oncogenes 

Many of the most powerful biological regulators of cell growth and proliferation are encoded by unstable mRNAs, which are targeted for rapid degradation by the cell. The loss of rapid degradation of these growth-promoting mRNAs can result in oncogenic transformation of the cell. Targeted degradation of proto-oncogene mRNAs and short-lived cytokines is controlled both by an AU-rich element (ARE) located in the 3' noncoding region, and by several proteins that bind the ARE sequence. Activation of the ARE for mRNA decay involves cotranslation of the mRNA by ribosomes, and employs the ubiquitin-proteasome pathway.[s]

Carcinogenesis typically results from a series of mutations that affect regulation of proliferation.
m1: inactivation of a tumor suppressor gene results in cell proliferation
m2: mutation inactivates a DNA repair gene
m3: mutation of a proto-oncogene generates an oncogene
m4: mutation inactivates more cancer suppressor genes, resulting in cancerous proliferation

Carcinogenic agents include:
Mutagenic carcinogens
Non-mutagenic carcinogens
Irradiation
Viruses (tumorigenic viruses) Transforming retroviruses and DNA tumor viruses encode oncogenes.
Genetic predisposition (Table of Hereditary Cancers)

Mutagenic carcinogens: ‘genotoxic’ carcinogens are DNA reactive and induce DNA damage. Tobacco smoke is probably the most notorious mutagenic carcinogen, producing, in addition to cardiovascular damage, cancers of the head and neck, lung, and bladder.

Non-mutagenic carcinogens: ‘non-genotoxic’ carcinogens are reported to have have significantly higher computed octanol/water partition coefficients than mutagenic carcinogens, suggesting that their ability to induce tumors may be associated with membraneous receptor sites and/or a longer residence time in the animal [r]. Estrogen can promote the growth of some breast cancers.

Irradiation:

Viruses: transforming retroviruses carry oncogenes mutated from cellular genes that are involved in mitogenic signaling and growth control. DNA tumor viruses encode oncogenes of viral origin that are essential for viral replication and cell transformation; viral oncoproteins complex with cellular proteins to stimulate cell cycle progression and led to the discovery of tumor suppressors. Viral systems support the concept that cancer development occurs by the accumulation of multiple cooperating events.[s]

Genetic predisposition: a variety of inherited genetic abnormalities render affected individuals more prone to malignancy. For example, hereditary non-polyposis colon cancer (HNPCC) is a form of colon cancer frequently associated with defects in the genes encoding MSH2 (about 35% of identified gene-defect cases) and MLH1 (about 60% of identified gene-defect cases). HNPCC is characterized by early age of onset and autosomal dominant inheritance with high penetrance. (Table of Hereditary Cancers)

∞ Cancer ∞ carcinogenesis ∞ oncogenes ∞ proliferation ∞ retroviruses ∞ signaling molecules ∞ tumorigenic viruses ∞ site map ∞

Tables  Apoptosis vs Necrosis  Apoptosis  Cell Adhesion  Cell signaling  Malignant Transformation  Oncogenes Proto-oncogenes  Regulatory Proteins Sequences  Table of Hereditary Cancers .

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posted 12/22/2010 at 12/22/2010 11:06:00 PM

cancer staging

Diagnostic evaluation of malignancy includes determination of the cancer's pathology (tissue type, organ of origin) in addition to staging of the cancer to determine degree of local, regional, and distant spread. Clinical and pathological staging is important to decisions concerning therapy, and to estimating prognosis (a statistical measure).

The stage of a cancer is influenced by:
¤ the carcinoma's biological aggressiveness
¤ time elapsed before clinical/pathologic diagnosis – c, cs = clinical; p, ps = pathological
¤ time elapsed before/since institution of anti-cancer treatment
¤ the tumor's sensitivity to cytotoxic therapies

Cancers commence as in situ colonies of cells that have escaped normal cellular controls. Local overgrowth of the primary tumor (localized) is followed by local tissue infiltration, and ultimately by malignant penetration of adjacent tissues (regional), blood vessels or lymphatics, with shedding and transport of malignant cells and ultimate colonization of distant organs (distant, secondary tumors, metastases).

Staging systems reflect this biological progression and the tissue type. The system of staging employed will depend, to some extent, upon the specific form of cancer involved – whether it is a solid tumor or hematologic, whether it belongs to a group staged by a specific system, such as the Ann Arbor staging classification that is commonly employed to stage lymphomas.

Cell type and grade is used to stage carcinomas of the brain and spinal cord.

TNM system – Tumor, Node, Metastasis
T refers to the primary (solid) tumor – X (cannot be evaluated), 'is' (in situ), 0 - 4 (size/extent)
N refers to regional lymph node involvement – X, 0-4 (extent)
M refers to metastasis – X, 0 = no metastasis, 1 = metastasis

Ann Arbor System (lymphomas)
Stage I – single region, typically a single lymph node and the surrounding area
Stage II – two regions on same side of diaphragm, an affected lymph node or organ within the lymphatic system and a second affected area
Stage III – both sides of diaphragm, including organ or area adjacent to lymph nodes or spleen
Stage IV – diffuse or disseminated involvement of one or more extralymphatic organs, including any involvement of the liver, bone marrow, or nodular involvement of the lungs.

Modifications to Ann Arbor
A = absence of constitutional symptoms
B = presence of constitutional symptoms (night sweats, fevers, unexplained weight loss of >10%)
E = "extranodal" (not in the lymph nodes) or spread from lymph nodes to adjacent tissue
X = largest deposit if >10 cm large ("bulky disease"), or mediastinum is wider than 1/3 of the chest on a chest X-ray

"Staging: Questions and Answers" at the National Cancer Institute
International Union Against Cancer, TNM

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posted at 12/22/2010 11:05:00 PM

c-Fos

The proto-oncogene c-fos participates in cellular proliferation by encoding a transcription factor, fos that forms homodimers, or heterodimers with the proto-oncogene c-jun (as AP1). The human homolog of the fos oncogene has been mapped to chromosome region 14q21→q31, and is overexpressed in a variety of cancers. Retrovirus-associated v-fos DNA sequences were originally isolated from murine sarcoma viruses, and fos is named for feline osteosarcoma virus.

AP1 : AP1 regulation : c-fos induction : c-jun : JNK : JNKK : MEK kinase : Rac : TPA responsive element : transcription response element : TREs : v-fos :

Induction of of c-fos expression by a variety of mitogens and differentiation-stimulating agents appears to be part of a general transcriptional response to growth factors. Expression of c-fos decreases during cellular differentiation in muscle, and is inhibited by the presence of MyoD and myogenin. Expression of c-fos is stimulated before the increased transcription of c-myc, ODC, and other proto-oncogenes. [s]

Activator protein 1 (AP1) of mammalian cells is a heterodimeric transcription factor formed by c-jun and c-fos associated in a structural motif known as a leucine zipper, which is required for DNA binding. The c-jun and c-fos subunits are held together by hydrophobic interactions between leucines located every 7th amino acid in an alpha-helix region of each subunit. [] 3D model of AP1 [] diagram []

The proto-oncogene, c-jun is a cellular immediate-early gene whose expression is rapidly induced by external stimuli such as epidermal growth factor (EGF), serum, 12-O-tetradecanoyl phorbol-13-acetate (TPA), nerve growth factor, and UV. Induced transcription of c-jun is independent of new protein synthesis.

The activator protein 1 (AP1) also results from dimeric complexes between members of the atf and maf protein families. Fos and jun are the commonest constituent proteins in mammalian cells. AP-1 activity is induced by growth factors, cytokines and oncoproteins. AP1 binds to transcription response elements (TPA responsive element, TREs) in the promotor region of several genes that regulate cell proliferation, survival, differentiation and transformation. Ionic interactions between terminal clusters of arginine molecules interact with DNA. Arginine is a basic amino acid with positively charged side-groups that interact with DNA's negatively charged phosphate moieties.

Regulation of AP-1 is complex and includes factors such as the composition of the dimers, the expression level of each monomer and post-transcriptional modification of the protein. AP1 can be activated by the induction of c-jun transcription. AP-1 proteins also interact with ancillary proteins that also regulate the activity of the complex.

Phosphorylation of AP1 by Jun N-terminal kinase (JNK) occurs at the N-terminal region of the c-jun protein. JNK activation is mediated through a signaling pathway that includes the small GTPase, Rac and the protein kinases, MEK kinase (MEKK) and JNKK.

AP1 : AP1 regulation : c-fos induction : c-jun : JNK : JNKK : MEK kinase : Rac : TPA responsive element : transcription response element : TREs : v-Fos : Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb : v-Fos : v-Sis : v-Myc : Tumor Suppressor Genes: TP53 :
Tables  Oncogenes Proto-oncogenes  Malignant Transformation  Regulatory Proteins Sequences  Cell signaling  Cell Adhesion  Apoptosis vs Necrosis  Apoptosis 

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posted at 12/22/2010 06:09:00 PM

c-Myc

The MYC proto-oncogene encodes the transcription factor, c-Myc protein, which binds DNA to regulate transcription. c-MYC is the cellular homolog of the retroviral v-myc oncogene, which when altered by chromosomal translocation, or amplification, or when exhibiting deregulated expression, plays a significant role in mutagenesis of tumors including bladder and breast cancers. c-Myc binds with a variety of protein interactors.

The c-Myc transcription factor is a helix-loop-helix leucine zipper protein that dimerizes with an obligate partner, Max, to bind DNA sites, 5'-CACGTG-3', termed E-boxes. c-Myc also binds DNA sites that vary from this palindromic hexanucleotide canonical sequence [3]. [s]

Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb : v-Fos : v-Sis : v-Myc :
Tumor Suppressor Genes: TP53
Tables  Oncogenes Proto-oncogenes  Malignant Transformation  Regulatory Proteins Sequences  Cell signaling  Cell Adhesion  Apoptosis vs Necrosis  Apoptosis 

. c-Myc Cancer Gene . Genome Biology .

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posted at 12/22/2010 11:01:00 AM

c-Sis

Human c-sis/PDGF-β proto-oncogene is overexpressed in a large percentage of human tumor cells involving a growth-promoting, autocrine growth circuit. The c-sis/PDGF-β promoter contains a unique homopurine/homopyrimidine sequence (SIS proximal element, SPE), which is crucial for transciption stimulating nuclear-binding factors.[1] The human sis gene is located at 22q12.3-13.1 on the long arm of chromosome 22.

: malignant pathology : non-malignant pathology : PDGF, platelet derived growth factor : v-sis :

The v-sis oncogene of the simian sarcoma virus is a retroviral homolog of the cellular gene encoding the β chain of PDGF (9,10) The hypothesis that unscheduled production of PDGF may contribute to the growth of spontaneous tumors is supported by the finding that PDGF is frequently produced by cell lines from human tumors such as glioblastoma and fibrosarcoma (11), melanoma (12), breast carcinoma (13), lung carcinoma (14), glioma (15), esophageal carcinoma (16) and Kaposi’s sarcoma (17). Gene transfer experiments have shown that overexpression of the normal human PDGF-β gene (c-sis, proto-oncogene) can cause the generation of fibrosarcoma (18), vascular connective tissue stroma with no necrosis (19) and tumorigenic and metastatic effects (20–22). [3]

Regulation of expression of platelet derived growth factor polypeptide B encoded by the c-sis proto-oncogene is important in a number of physiological and pathological conditions.[2] Sequences upstream of the c-sis RNA CAP site respond to the HTLV-I transactivator protein to increase RNA synthesis from either the c-sis or HTLV I promoter. [2]

Platelet-derived growth factor (PDGF) is a ubiquitous, potent mitogen and chemotactic factor for many connective tissue cells. PDGF occurs as a three-disulfide-linked dimer composed of two homologous chains, α and β (1,2). The biological function of PDGF is mediated through binding to two cell surface proteins, PDGF receptors α and ß (3–5). Binding of PDGF to the extracellular part of either receptor type leads to dimerization of receptor molecules, followed by activation of the receptor protein-tyrosine kinase (6) and generation of phosphorylation-mediated signals that initiate the biological response (7,8).

PDGF has been implicated in the pathogenesis of several non-malignant proliferative diseases including atherosclerosis (23–24), fibrosis (25), restenosis following vascular angioplasty (26), giant cell arteritis (27), aseptic loosening (28) and bronchiolitis obliterans syndrome (29). [3]

: malignant pathology : non-malignant pathology : PDGF, platelet derived growth factor : v-sis :
Tables  Oncogenes Proto-oncogenes  Malignant Transformation  Regulatory Proteins Sequences  Cell signaling  Cell Adhesion  Apoptosis vs Necrosis  Apoptosis 

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posted at 12/22/2010 05:16:00 AM

Against Religious Malignancy

Religion is not the only cause of malignant behavior on the planet, but it is a cause that is rooted in irrationality and too often promotes intolerance while claiming the high moral ground. Join the best atheist themed blogroll!A-Deistic
Adeistic
Black Out
cosmos
Eine Kleine Nattermusing
eMusings
eVolition
Galaria
Godborygmi
Godspell Follies
Gray Matters
MetaThoughts
Mimble Wimble
Naturalism
bLogodaedaly
palimpsest
Salient
Science of Evolution
Sechuam
Sintheist
Tabula Flexuosa
The Scarlet A
Weltschauung

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posted 1/01/2008 at 1/01/2008 01:30:00 PM

estrogen receptors

Estrogen receptors (ERs) are located in the nucleus of estrogen-sensitive tissues (breast, endometrium, brain, bone, liver, heart). When the steroid hormone estrogen enters the nucleus of receptive tissues, it forms complexes with estrogen receptors, which then bind to estrogen response elements of DNA, activating expression of genes via stimulation of co-activators. The effects of estrogen stimulation vary from one tissue to another (pleiotropy).

anti-estrogenic drugs : cancers : co-activators, co-regulators, co-repressors : ERs : pleiotropy : raloxifene : selective estrogen receptor modulators : SERMs : Tamoxifen :

Two subtypes of estrogen receptors, ERα and ERβ, are known to mediate estrogen signaling through their function as ligand-dependent transcription factors [4]. After crossing the cellular membrane, estrogens bind to receptors ERα and ERβ, leading to receptor activation.

ERs interact with cis-regulatory elements of target genes:
a) by direct binding to conserved estrogen response elements (EREs; 5'-GGTCANNNTGACC-3', where N is any nucleotide), or
b) indirectly through association with AP1 or Sp1 transcription factor complexes and their respective binding sites [5-9].

Co-activators and co-repressors complex with estrogen receptors to regulate estrogen responses [10]. Cyclical turnover of transcriptional complexes and estrogen receptors at the regulatory elements of target genes provides an additional regulatory mechanism [11-13].

Potential mechanisms for the observed pleiotropic effects of estrogens include tissue-specific distribution of co-regulators, associated transcription factors complexes, and receptor subtypes and splice variants [14]. The consequence of ER activation appears to be alterations in transcriptional activity and expression profiles of target genes. Several genes, including those for trefoil factor 1/pS2, cathepsin D, cyclin D1, c-Myc and progesterone receptor, are positively regulated by ERα [15-20].[fft-s]

Because estrogen can stimulate cellular proliferation in tissues with estrogen-receptors, it is associated with increased risk of breast and endometrial carcinomas in replicating cells. Anti-estrogen chemotherapeutic agents compete with estrogen for binding to estrogen receptors, blocking estrogen activation of oncogenes. Selective estrogen receptor modulators, or SERMs, are a class of anti-estrogen drugs that selectively stimulate or inhibit the estrogen receptors of different target tissues.

Tamoxifen was the first SERM employed as an adjuvant treatment of estrogen receptor-positive breast cancers. It exerts an antiestrogenic effect by binding to the estrogen receptors of breast cells, preventing binding to coactivators and thus preventing activation of cell proliferation oncogenes. Because Tamoxifen stimulates endometrial estrogen receptors, increasing the risk of endometrial carcinoma, its use is restricted to treatment and it is not employed for prophylaxis of breast cancers. Another SERM, raloxifene is used to prevent osteoporosis and has demonstrated effectiveness against breast cancer without the problematic endometrial stimulation of Tamoxifen.

anti-estrogenic drugs : cancers : co-activators, co-regulators, co-repressors : ERs : pleiotropy : raloxifene : selective estrogen receptor modulators : SERMs : Tamoxifen :

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posted 12/20/2007 at 12/20/2007 05:06:00 AM

gene amplification

Gene amplification involves the production of multiple copies of a gene through repeated copying of the gene.

Amplification is distinct from duplication, which is precise genome doubling preparatory to cell division, and from endoreduplication, which leads to endopolyploidy. When many copies of the amplified region are produced, they can form their own small pseudo-chromosomes called 'double-minute chromosomes'.

Gene amplification results from dysfunction in malignant cell lines. However, some organisms have evolved mechanisms for gene amplification in order to provide needed gene products in large quantities. Such functional mechanisms include:
a. The elaboration of small "extrachromosomal" units that replicate to high copy number (rDNA);
b. Tandem gene duplications (DHFR);
c. Localized endoreduplication of chorion genes.

Different organisms employ different mechanisms. Sometimes, as for double-minute chromosomes and human secretin receptor gene* (HSR), more than one mechanisms is employed within an organism.

Some mutants in developmentally expressed genes of plants result from heritable gene amplification. Gene amplification can be regulated developmentally, temporally, or environmentally.

Neoplastic cells can amplify, or copy, DNA segments in response to cellular signals or environmental events. When an oncogene is included in the amplified region, then the resulting overexpression of the oncogene gene leads to deregulated cell growth. Examples include amplification of the MYC oncogene in a wide range of tumors, and amplification of the ErbB-2 or HER-2/neu oncogene in breast and ovarian cancers. Clinical treatments have been designed to target cells overexpressing the HER-2/neu oncogene protein product.

Resistance of cancer cells to chemotherapeutic agents is linked to amplification of the gene that prevents absorption of the drug by the cell. A gene called MDR, for 'multiple drug resistance', is commonly involved. The protein product of the MDR gene acts as a membrane pump that selectively ejects molecules, including chemotherapy agents, rendering the drugs ineffective.

* the human secretin receptor (hSR) is an important glycoprotein receptor involved in regulation of the secretion of pancreatic bicarbonate, water, and electrolytes.

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posted 12/18/2007 at 12/18/2007 11:11:00 PM

immune evasion

Tumors employ a variety of mechanisms to evade the immune system.

Evasive mechanisms range from a passive failure to express major histocompatibility complexes (MHC) and co-stimulatory molecules 4,5 to active strategies such as the production of immunosuppressive cytokines and other factors 6,7 . Passive and active processes are also involved in the Fas counterattack.[s]

The Fas ligand (FasL, C95L) is expressed by cells of the lymphoid/myeloid series and by non-lymphoid cells, where it contributes to the 'immune privilege' of cancer cells by inducing apoptosis in infiltrating proinflammatory immunocytes 9,10. Simultaneously, many cancer cells are relatively resistant to Fas-mediated apoptosis.

This resistance to Fas-mediated apoptosis might be a result of downregulation of Fas, or release of soluble Fas, or of abnormalities in the level of several signal transduction cascade proteins. Neoplastic Fas resistance might also result from downregulation of caspase 1, Bax or Bak, and upregulation of FLIP, FAP-1 or Bcl2. Further, some components of the pathway exhibit mutations, including Fas itself and caspase 8. Some mutations of oncogenes and tumor suppressor genes, which are commonly found in tumors, could impair Fas signaling (p53 and Ras) or could cooperate with Fas resistance (c-Myc) in certain tumor cells. Many cancer cells express FasL, so are able to counterattack and kill Fas-sensitive tumor- infiltrating lymphocytes (TILs).[s]

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posted 12/16/2007 at 12/16/2007 11:11:00 AM

metastasis

Metastasis is cell motility run amok.

Malignant tumors exhibit not only uncontrolled proliferation and local invasion, but the ability to set up distant colonies. Growth and survival of metastatic tumor cells depend upon angiogenesis and the ability of tumor cells to evade detection by the immune system.

Metastasizing cells escape normal cellular adhesion mechanisms and shed from the primary tumor. Local invasion can enable the 'escapee' cells to penetrate lymphatics and/or blood vessels. Local infiltration of lymph nodes is associated with an increased likelihood of metastasis, so determination of whether or not lymph nodes are involved is important in cancer staging.

Having been transported via circulation of lymph or blood, the malignant cells invade distant tissues where they establish focal colonies of proliferating cells (secondaries). Tumors originating in certain tissues often display a propensity for metastasis to specific tissues and organs.

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posted 12/12/2007 at 12/12/2007 07:04:00 PM

mitogens

A Mitogen, or somatomedin, is any molecules that stimulates a cell to divide. Most mitogens are proteins, and they stimulate signal transduction pathways that utilize mitogen activated protein kinases. Mitogens include cytokines, growth factors, hormones, neurotransmitters, cellular stress proteins, and cell adhesion ligands. For example, antigen stimulation of cell adhesion immunoglobulins triggers mitosis in B cells.

Mitogen activated protein kinases (MAP kinases) act as switch kinases that transmits information of increased intracellular tyrosine phosphorylation to that of serine/threonine phosporylation. MAPK-activated protein kinases (or MKs; formerly MAPKAP kinases) respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs.(ffta)

The signaling cascade is:
mitogen → MAPKK kinase (MAPKKK) → MAPK kinase (MAPKK) → MAP kinase (MAPK) → signaling

Among the substrates of ERK are the members of the p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases (10). RSK plays an active role in nuclear signaling by phosphorylating the cyclic AMP response element binding protein (CRE-binding protein, CREB) (33), c-Fos (5), and IB (27). Phosphorylation of Bad (3, 29) and C/EBPß (4) by RSK can protect cells from apoptosis. RSK has also been implicated in cell cycle regulation. RSK phosphorylates histone H3 (25), suggesting that RSK may regulate chromatin remodeling.[s-fft]

MAP kinases are also called ERKs for extracellular-signal regulated kinases, microtubule associated protein-2 kinase (MAP-2 kinase), myelin basic protein kinase (MBP kinase), ribosomal S6 protein kinase (RSK-kinase) and EGF receptor threonine kinase (ERT kinase). Maximal MAP kinase activity requires phosphorylation of both tyrosine and threonine residues. Activators of the extracellular-signal regulated kinase family (ERKs) of MAPKs include the mitogens, Ras [fft], polypeptide growth factors PDGF, CSF-1, IGF-1, EGF insulin, PMA.

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posted at 12/12/2007 03:04:00 PM

neoplastic mutations

Mutation of proto-oncogenes may convert them to oncogenes, while mutation of tumor suppressor genes may cause a loss of anti-proliferative functions.

Based on computational analysis of mutations affecting CAN-genes (candidate cancer genes) in breast and colorectal carcinomas, it has been estimated that cancers average 17 mutations (mostly SNPs) occurring within at least 90 genes [↓]. Cancers originating in the same tissue display mutation of different genes, and mutated genes contributing to breast cancer are different from genes mutated in colorectal cancers. Many of the mutated genes are involved in pathways involved in cell adhesion, cell movement, and cell signaling. Because each of the affected pathways incorporates multiple genes, mutations in different genes within a pathway could have similar consequences.

G-T mismatch in the Ras proto-oncogene can cause an alteration of the amino acid at position 12 from glycine to valine, causing the Ras oncogene-encoded G-protein to remain continuously activated when it cannot release GTP. Mutations that prevent GTP hydrolysis favor constitutive activation as RAS-GTP, RasD. The commonest mutations are at the 12 (Gly→Val) → GAP insensitive, and the 61 positions → stabilizing against GTP hydrolysis.

The Consensus Coding Sequences of Human Breast and Colorectal Cancers.
The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we have determined the sequence of well-annotated human protein coding genes in two common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ~90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J,
Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Science. 2006 Sep 7; [Epub ahead of print] HHMI news.


[Analysis, identification and correction of some errors of model refseqs appeared in NCBI Human Gene Database by in silico cloning and experimental verification of novel human genes] [Yi Chuan Xue Bao. 2004] PMID: 15478601
Genetic alterations in the adenoma--carcinoma sequence. [Cancer. 1992] PMID: 1516027
Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells. [Int J Cancer. 2001] PMID: 11391615
Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. [Am J Hum Genet. 2006] PMID: 16685647
Causes and consequences of microsatellite instability in endometrial carcinoma. [Cancer Res. 1999]

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posted 12/11/2007 at 12/11/2007 07:11:00 PM

NF-κB

NF-κB is an important regulator of cell proliferation, cellular survival, and the inflammatory and immune responses. Within the nucleus, the NF-κB transcription factor promotes the expression of specific genes regulated by NF-κB DNA-binding sites.

The enzyme IκB kinase (IKK) stimulates phosphorylation of two serine residues in the regulatory domain of Inhibitor of kappa B (IκB), targetting the IκB molecules for ubiquitin/proteasome degradation, and releasing NF-κB from inhibition as cytoplasm-sequestered NF-κB dimers.

Many tumor types have chronically active NF-κB, resulting from:
● mutations in genes encoding the NF-κB transcription factors themselves, or
● mutations in genes that control NF-κB activity

Several viruses, including HIV/AIDS, control the expression of viral genes through viral binding sites for NF-κB, thus contributing to viral replication or viral pathogenicity. For HIV-1, activation of NF-κB could be related to activation of the virus from a latent, inactive state.

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posted at 12/11/2007 06:13:00 PM

oncogenes

Alteration of a gene that normally controls cell growth can promote the uncontrolled growth characteristic of cancer. The normal form of the gene is termed a proto-oncogene, and the malignantly transformed gene is termed an oncogene.

Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb :
Tumor Suppressor Genes: TP53

Damaged genes are passed down through the cancer cell line, and may be dominant or recessive genes:

Recessive: tumor suppressors, growth suppressors, recessive oncogenes or anti-oncogenes. Malignant transformation can result from genetic damage to genes coding for growth factors, growth factor receptors and/or proteins for signal transduction cascades.

Dominant: Proto-oncogenes participate in a variety of normal cellular functions, but have the potential to tranform into cellular oncogenes when damaged. Proto-oncogenes normally function in the various signal transduction cascades that regulate cell growth, proliferation and differentiation. Cellular proto-oncogenes resident in transforming retroviruses are designated as c- (cellular origin) as opposed to v- (retroviral origin). Oncogenes are malignantly transformed proto-oncogenes - table  Oncogenes Proto-oncogenes

14-3-3 proteins are a family of highly conserved cellular proteins that play key roles in the regulation of central physiological pathways. More than 200 14-3-3 target proteins have been identified, including proteins involved in mitogenic and cell survival signaling, cell cycle control and apoptosic cell death. Importantly, the involvement of 14-3-3 proteins in the regulation of various oncogenes and tumor suppressor genes points to a potential role in human cancer. Tzivion G, Gupta VS, Kaplun L, Balan V. 14-3-3 proteins as potential oncogenes. Semin Cancer Biol. 2006 Jun;16(3):203-13. Epub 2006 Apr 1.

Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb :
Tumor Suppressor Genes: TP53
Proto-oncogene/oncogene families ● growth factor genes ● receptor tyrosine kinases ( RTKs) ● membrane ssociated non-receptor tyrosine kinases (PTKs) ● G-protein coupled receptors (GPCRs) ● Serine/Threonine Kinases ● nuclear DNA-binding/transcription factors ●

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posted 12/10/2007 at 12/10/2007 09:30:00 PM

proliferation

Cellular reproduction and programmed cell death (apoptosis) are normally closely regulated within populations of cells. Cell numbers increase when cellular reproduction outpaces cell death, and such cellular proliferation is normal under some circumstances, such as clonal expansion as part of the immune response.

However, tumors arise when cell proliferation escapes normal cellular controls. Benign tumors expand locally, but lack the other defining characteristic of malignancy, which is invasiveness both locally and at a distance (metastasis).

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posted 12/09/2007 at 12/09/2007 08:09:00 AM

p53

Tumor suppressor genes encode proteins that reduce the risk that a eukaryotic cell line will become tumorigenic. When tumor suppressor proteins are sequestered away from their normal functional locations within the cell by retroviral tumor antigens, the loss of their normal suppressor functions results in cellular transformation.

The tumor suppressor gene, TP53 represents an exception to an exclusive 'two-hit hypothesis' in that a single defective p53 gene is sufficient to increase susceptibility to tumorigenesis. The TP53 gene was originally identified as a major nuclear antigen in transformed cells, but mutant forms of the p53 protein interfere with cell growth suppressor effects of wild-type p53, indicating that the p53 gene product is actually a tumor suppressor. p53 is the single most identified mutant protein in human tumors, and 50% of cancers have missense point mutations in the TP53 gene.

In normal resting cells p53 is inactive and bound to the protein MDM2. This prevents both its activation and promotes p53 degradation by acting as ubiquitin ligase (Ub ligase). The transcription factor p53 is activated when MDM2 is inhibited by signaling by factors such as DNA damage. Once activated, p53 acts as a tumor suppressor gene by virtue of its apoptotic function. Active p53 induces the transcription of many genes, including Bax, which promotes apoptosis by stimulating the release of cytochrome c and apoptosome formation.

MDM2 production is induced by negative feedback from p53, and some oncogenes inhibit MDM2 activity by stimulating the transcription of MDM2-binding proteins. The Hsp90 interacts with the p53 protein in vivo. Human papillomavirus (HPV) encodes for the protein E6, which binds the p53 protein and inactivates it. This inactivation of p53, in synergy with the inactivation of another cell cycle regulator, p105RB, stimulates repeated cell division manifestested in HPV infection (a tumorigenic virus).

Damage to DNA by mutagens 'alerts' cell-cycle checkpoints, stimulating expression of ATM, CHK1, CHK2, and p14ARF proteins, and causing phosphorylation of p53 close to the MDM2 binding site. The activated TP53 gene produces several proteins, including p21 that binds to the G1-S/CDK and S/CDK complexes that are necessary for cell cycle progression G1 → S.

p53 protein suppresses tumors by:
1. activating DNA repair proteins
2. halting the cell cycle at the G1/S regulation point (DNA damage recognition) – via p21.
2. initiating apoptosis, programmed cell death, if DNA damage is irreparable.

DNA-damage checkpoints monitor DNA damage before the cell enters S phase (G1 checkpoint); during S phase, and after DNA replication (G2 checkpoint). Increased levels of CDK-molecules and cyclins are sometimes found in human cancers. CDK-molecules and cyclins collaborate with the products of tumour suppressor genes, such as p53 and Rb, during the cell cycle. The p53 protein senses DNA damage and can halt progression of the cell cycle in G1. Both copies of the p53 gene must be mutated for cycle arrest to fail completely, so mutations in p53 are recessive and p53 qualifies as a tumor suppressor gene. The protein generated by the p53 gene acts as a signal for apoptotic cell death when DNA damage is too extensive for repair mechanisms.

¤ Cancer ¤ carcinogenesis ¤ oncogenes ¤ proliferation ¤ retroviruses¤ signaling molecules ¤ tumor suppressors ¤ tumorigenic viruses ¤ Tables  Malignant Transformation  Oncogenes Proto-oncogenes  Regulatory Proteins Sequences  Apoptosis vs Necrosis  Apoptosis  Cell Adhesion  Cell signaling □ Familial Cancer Syndromes and Tumor Suppressors □
Џ animation How Tumor Suppressor Genes Block Cell Division .

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posted at 12/09/2007 05:03:00 AM

Ras

Ras genes encode proteins of the Ras superfamily, which are important molecular switches in signal transduction pathways. Ras proteins are involved in cell adhesion, apoptosis, cell migration, cytoskeletal integrity, cell proliferation, and, when unregulated, neoplasia.

activation/inactivation : amplification : DGKzeta : GAPs : GEFs : mutations : Rab: Ras superfamily : Ras : RasGAP : RasGRP : Rho : superfamily :

The superfamily includes Ras, Rho, and Rab families. The Rho family includes Rho-GTPase. [] inactive and active Ras molecular switch [] Once activated by binding to GTP (Rho-GTP), Rho GTPases interact with cellular target effector proteins to drive axonal guidance, reorganization of the actin cytoskeleton (morphogenesis, cell polarity, cell movement, and cytokinesis), regulation of gene expression, chemotaxis, cell cycle progression, oncogenic transformation, and epithelial wound repair.

Ras is a small GTPase (G-protein), a regulatory GTP hydrolase that cycles between activated (RAS-GTP) and inactivated (RAS-GDP) conformations. [] 3D inactive and active Ras molecular switch []Ras is activated by guanine exchange factors (GEFs) such as CDC25, SOS1 and SOS2, and SDC25 in yeast. The GEFs are activated by mitogenic signals and through feedback from Ras itself.

Ras is inactivated by GTPase-activating proteins (GAPs), including RasGAP. This activating protein increases the rate of GTP hydrolysis and converts Ras from the active GTP-bound conformation to the inactive GDP-bound form (releasing Pi).

Diacylgycerol kinase zeta (DGKzeta) regulates factors that promote activity of the oncogene product, Ras, the activity of which must be precisely regulated lest abnormal cellular proliferation result. An estimated 30% of human tumors have an activating mutation of the Ras gene. Guanine nucleotide exchange factors (GEFs) activate Ras by facilitating GTP binding. Abnormally high levels of the nucleotide exchange factor, RasGRP (RAS-GAP) can lead to malignant transformation. RasGRP has a diacylglycerol (DAG)-binding domain and its exchange factor activity depends on local availability of the signaling molecule DAG. Diacylglycerol kinases(DGKs) remove DAG from the cell by converting DAG to PA. DGKzeta, but not other DGKs, can completely eliminate Ras activation induced by RasGRP, and diacylglycerol kinase activity is required for this mechanism.

Ras is attached to the cell membrane by prenylation. It normally functions in pathways that couple growth factor receptors to downstream mitogenic effectors that are involved in cell proliferation or cellular differentiation. Ras activates several pathways, of which the mitogen-activated protein MAP kinase pathway is important. MAPKs transmit signals downstream to other protein kinases and gene regulatory proteins.

Mutations of Ras proto-oncogenes are common → H-RAS, N-RAS, and K-RAS oncogenes. Inappropriate activation of the Ras gene plays a key role in signal transduction, proliferation, and malignant transformation. Oncogenes such as p210BCR-ABL and the growth receptor erbB are located upstream of Ras, so their signals will transduce through Ras should they be constitutively activated. The tumour suppressor gene NF1 encodes a RAS-GAP (Ras-GRP), and its mutation in neurofibromatosis renders Ras less likely to be inactivated.

Point mutations can transform Ras into oncogenes such that its GTPase reaction can no longer be stimulated by GAP, increasing the half life of active Ras-GTP mutants. Mutations that prevent GTP hydrolysis favor constitutive activation as RAS-GTP, RasD. The commonest mutations are at the 12 (Gly→Val) → GAP insensitive, and the 61 positions → stabilizing against GTP hydrolysis.

Ras amplification occurs only occasionally in tumours. Unfortunately, the sequence differences between Ras proto-oncogenes and Ras oncogenes are so slight (typically single amino acid changes) that drug targetting abnormal Ras will prove very difficult.

activation/inactivation : amplification : DGKzeta : GAPs : GEFs : mutations : Rab: Ras superfamily : Ras : RasGAP : RasGRP : Rho : superfamily :

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posted 12/07/2007 at 12/07/2007 11:05:00 PM

hit tracker . . . proliferating since 10/06/06