Tumor Suppressors


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Introduction

Tumor suppressor genes were first identified by making cell hybrids between tumor and normal cells. On some occasions a chromosome from the normal cell reverted the transformed phenotype. Several familial cancers have been shown to be associated with the loss of function of a tumor suppressor gene. The table below lists several of these syndromes. A few of these tumor suppressor genes are described in more detail below. They include the retinoblastoma susceptibility gene (RB), Wilms' tumors (WT1), neurofibromatosis type-1 (NF1), familial adenomatosis polyposis coli (FAP), von Hippel-Lindau syndrome (VHL), and those identified through loss of heterozygosity such as in colorectal carcinomas (called DCC for deleted in colon carcinoma) and P53 which was originally thought to be a proto-oncogene. However, the wild-type P53 protein suppresses the activity of mutant alleles of p53 which are the oncogenic forms of P53.

 

 

 

 

 

 

 

 

 

 


Familial Cancer Syndrome Tumor Suppressor Gene Function Chromosomal Location Tumor Types Observed
Li-Fraumeni Syndrome P53 cell cycle regulation, apoptosis 17p13.1 brain tumors, sarcomas, leukemia, breast cancer
Familial Retinoblastoma RB1 cell cycle regulation 13q14.1-q14.2 retinoblastoma, osteogenic sarcoma
Wilms Tumor WT1 transcriptional regulation 11p13 pediatric kidney cancer, most common form of childhood solid tumor
Neurofibromatosis Type 1 NF1, protein = neurofibromin 1 catalysis of RAS inactivation 17q11.2 neurofibromas, sarcomas, gliomas
Neurofibromatosis Type 2

GeneReviews
NF2, protein = merlin or neurofibromin 2 linkage of cell membrane to actin cytoskeleton 22q12.2 Schwann cell tumors, astrocytomas, meningiomas, ependymonas
Familial Adenomatous Polyposis APC signaling through adhesion molecules to nucleus 5q21-q22 colon cancer
Tuberous sclerosis 1

GeneReviews
TSC1, protein = hamartin forms complex with TSC2 protein, inhibits signaling to downstream effectors of mTOR 9q34 seizures, mental retardation, facial angiofibromas
Tuberous sclerosis 2

GeneReviews
TSC2, protein = tuberin see TSC1 above 16p13.3 benign growths (hamartomas) in many tissues, astrocytomas, rhabdomyosarcomas
Deleted in Pancreatic Carcinoma 4, Familial juvenile polyposis syndrome

GeneReviews
DPC4, also known as SMAD4 regulation of TGF-β/BMP signal transduction 18q21.1 pancreatic carcinoma, colon cancer
Deleted in Colorectal Carcinoma DCC transmembrane receptor involved in axonal guidance via netrins 18q21.3 colorectal cancer
Familial Breast Cancer

GeneReviews
BRCA1 functions in transcription, DNA binding, transcription coupled DNA repair, homologous recombination, chromosomal stability, ubiquitination of proteins, and centrosome replication 17q21 breast and ovarian cancer
Familial Breast Cancer

GeneReviews
BRCA2:
same as the FANCD1 locus
transcriptional regulation of genes involved in DNA repair and homologous recombination 13q12.3 breast and ovarian cancer
Cowden syndrome

GeneReviews
PTEN = phosphatase and tensin homolog phosphoinositide 3-phosphatase, protein tyrosine phosphatase 10q23.3 gliomas, breast cancer, thyroid cancer, head & neck squamous carcinoma
Peutz-Jeghers Syndrome (PJS)

GeneReviews
STK11 (serine-threonine kinase 11), a nuclear localized kinase, was also called STK11 phosphorylates and activates AMP-activated kinase (AMPK), AMPK involved in stress responses, lipid and glucose meatabolism 19p13.3 hyperpigmentation, multiple hamartomatous polyps, colorectal, breast and ovarian cancers
Hereditary Nonpolyposis Colon Cancer type 1, HNPCC1

GeneReviews
MSH2 DNA mismatch repair 2p22-p21 colon cancer
Hereditary Nonpolyposis Colon Cancer type 2, HNPCC2

GeneReviews
MLH1 DNA mismatch repair 3p21.3 colon cancer
Familial diffuse-type gastric cancer

GeneReviews
CDH1, protein = E-cadherin cell-cell adhesion protein 16q22.1 gastric cancer, lobular breast cancer
von Hippel-Lindau Syndrome VHL regulation of transcription elongation through activation of a ubiquitin ligase complex 3p26-p25 renal cancers, hemangioblastomas, pheochromocytoma, retinal angioma
Familial Melanoma

CDKN2A = tumor suppressor:
protein = cyclin-dependent kinase inhibitor 2A
gene produces 2 proteins: p16INK4 and p14ARF
p16INK4 inhibits cell-cycle kinases CDK4 and CDK6; p14ARF binds the p53 stabilizing protein MDM2 9p21 melanoma, pancreatic cancer, others
Gorlin Syndrome: Nevoid basal cell carcinoma syndrome (NBCCS)

GeneReviews
PTCH, protein = patched transmembrane receptor for sonic hedgehog (shh), involved in early development through repression of action of smoothened 9q22.3 basal cell skin carcinoma
Multiple Endocrine Neoplasia Type 1

GeneReviews
MEN1 intrastrand DNA crosslink repair 11q13 parathyroid and pituitary adenomas, islet cell tumors, carcinoid

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P53

Loss of heterozygosity at the short arm of chromosome 17 has been associated with tumors of the lung, colon and breast. This region of chromosome 17 includes the P53 gene. The inheritance of a mutated P53 allele is the cause of Li-Fraumeni syndrome (LFS). LFS is a disorder that greatly increases the risk of several types of cancer including sarcomas, breast cancers, acute leukemias and brain tumors. The disorder is named for the two physicians who first recognized and described the syndrome: Frederick Pei Li and Joseph F. Fraumeni, Jr.

The P53 gene was originally discovered because the protein product complexes with the SV40 large T antigen. It was first thought that P53 was a dominant oncogene since cDNA clones isolated from tumor lines were able to cooperate with the RAS oncogene in transformation assays. This proved to be misleading since the cDNA clones used in all these studies were mutated forms of wild-type p53 and cDNAs from normal tissue were later shown to be incapable of RAS co-transformation. The mutant p53 proteins were shown to be altered in stability and conformation as well as binding to hsp70.

Subsequent analysis of several murine leukemia cell lines showed that the P53 locus was lost by either insertions or deletions on both alleles. This suggested that wild-type p53 may be a tumor suppressor not a dominant proto-oncogene. Direct confirmation came when it was shown that wild-type p53 could suppress transformation in oncogene cooperation assays with mutant p53 and ras.

It has now been demonstrated that mutation at the P53 locus occurs in cancers of the colon, breast, liver and lung. Indeed, p53 involvement in neoplasia is more frequent than any other known tumor suppressor or dominant proto-oncogene.

The protein encoded by P53 is a nuclear localized phosphoprotein. A domain near the N-terminus of the p53 protein is highly acidic like similar domains found in various transcription factors. When this domain is fused to the DNA-binding domain of the yeast GAL4 protein, the resulting chimera is able to activate transcription from genes containing GAL4 response elements. This suggested that p53 is likely to be involved in transcriptional regulation. Indeed, sequences at the N-terminus of the p53 protein have been shown to function as a transcription activator. Subsequent research demonstrated that p53 regulates the transcription of genes involved in suppression of cell growth. p53 binds to DNA sequences containing two copies of the motif: 5'-PuPuC(A/T)(A/T)GPyPyPy-3' (Pu = any purine; Py = any pyrimidine). This sequence motif indicated that that p53 bound to DNA as a tetramer. Binding as a tetrameric complex explains the fact that mutant p53 proteins act in a dominant manner to interfere with the activity of wild-type proteins present in the tetrameric complex.

Like pRB, p53 forms a complex with SV40 large T antigen, as well as the E1B transforming protein of adenovirus and E6 protein of human papilloma viruses. Complexing with these tumor antigens increases the stability of the p53 protein. This increased stability of p53 is characteristic of mutant forms found in tumor lines. The complexes of T antigens and p53 renders p53 incapable of binding to DNA and inducing transcription. A cellular protein, originally identified in a spontaneous transformed mouse cell line and termed MDM2, has been shown to bind to p53. Complexing of p53 and MDM2 results in loss of p53 mediated trans-activation of gene expression. Significantly, amplification of the MDM2 gene is observed in a significant fraction of most common human sarcomas. The MDM2 protein is a key regulator of p53 function and does so because the protein is a ubiquitin ligase that ubuiquitinates p53 when the two proteins are complexed together. This ubiquitination leads to proteosome-mediated degradation of p53. Several other ubiquitin ligases ensure that p53 activity is kept in check by ensuring it has a very short half-life in the cells. These other ubiquitin ligases incclude C-terminus of Hsc70 interacting protein (CHIP), p53-induced RING-H2 (PirH2), and constitutive photomorphogenesis protein 1 (COP1; also called ring finger and WD repeat domains-containing protein 2, RFWD2).

The transciptional activity of p53 is regulated by various post-translational mechanisms including phosphorylation, acetylation, methylation, and ubiquitinylation. Under normal cellular conditions the level of p53 is low following mitosis but increases during G1. During S-phase the protein becomes phosphorylated by the M-phase cyclin-CDK complex of the cell cycle This phosphorylation of p53 allows it to dissociate from MDM2 and migrate to the nucleus and activate the expression of target genes (see Figure below).

Under conditions of cellular stress, or when DNA is damaged by ionizing or uv irradiation, various kinases become activated and result in the hyperphosphorylation of p53 dramtically increasing p53-mediated transcription. These stress-induced and DNA damage-induced kinases include ataxia telangiectasia mutated kinase (ATM), ataxia telangiectasia and Rad3-related protein (ATR), casein kinase I (CKI), and AMPK. One major cell-cycle regulating gene that is a target for p53 is the CDK inhibitory protein (CIP), p21CIP. Activation of p53, particularly in response to stress or DNA-damage, results in increased expression of p21CIP. Expression of p21CIP leads to cell cycle arrest at several points as indicated in the Figure below.

Transcriptional regulation of p21 gene by p53 and resultant effects on cell cycle progression

Activation of p53 by cellular stress and DNA damage. Normal regulation of the level of p53 protein is carried out by various ubiquitin ligases (e.g. MDM2) that ubiquitinate p53 resulting in its degradation in the proteosome. In response to DNA damage, or cellular stress, several kinases become activated that hyperphosphorylate p53 allowing the protein to be released from MDM2. Phospho-p53 enters the nucleus and activates the transcription of many target genes, with the CDK inhibitory protein (CIP) gene, p21CIP being shown. Increased levels of p21CIP results in inhibition of several cyclin-CDK complexes causing cell cycle arrest.

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Retinoblastoma (RB)

In the familial form of this disease individuals inherit a mutant, loss of function allele from an affected parent. A subsequent later somatic mutational event inactivates the normal allele resulting in retinoblastoma development. This leads to an apparently dominant mode of inheritance. The requirement for an additional somatic mutational event at the unaffected allele means that penetration of the defect is not always complete.

In sporadic forms of tumors involving the RB locus 2 somatic mutational events must occur, the second of which must occur in the descendants of the cell receiving the first mutation. This combination of mutational events is extremely rare.

The locus of the RB gene, identified cytogenetically, is chromosome 13q14.1. A 4.7 kb RB transcript has been identified (by chromosomal walking and subsequent Northern blotting with genomic DNA probes) and subsequently cloned. The RB gene encompasses 27 exons that span 180 kb of chromosome 13. Two of the introns in this gene are extremely large, 35 kb and 70 kb. The RB RNA encodes a p110 kDa protein (pRB) of 928 amino acids. pRB is a nuclear localized phosphoprotein. pRB is not detectable in any retinoblastoma cells. However, surprisingly detectable levels of pRB can be found in most proliferating cells even though there is a restricted number of tissues affected by mutations in the RB gene (i.e. retina, bone and connective tissue).

Many different types of mutations occur to result in loss of RB function. The largest percentage (30%) of retinoblastomas contain large scale deletions. Splicing errors, point mutations and small deletions in the promoter region have also been observed in some retinoblastomas.

The germ line mutations at RB occur predominantly during spermatogenesis as opposed to oogenesis. However, the somatic mutations occur with equal frequency at the paternal or maternal locus. In contrast, somatic mutations at RB in sporadic osteosarcomas occur preferentially at the paternal locus. This may be the result of genomic imprinting.

The major function of pRB is in the regulation of cell cycle progression. Its ability to regulate the cell cycle correlates to the state of phosphorylation of pRB. Phosphorylation is maximal at the start of S phase and lowest after mitosis and entry into G1. Stimulation of quiescent cells with mitogen induces phosphorylation of pRB, while in contrast, differentiation induces hypophosphorylation of pRB. It is, therefore, the hypophosphorylated form of pRB that suppresses cell proliferation. One of the most significant substrates for phosphorylation by the G1 cyclin-CDK complexes that regulate progression through the cell cycle is pRB. pRB forms a complex with the E2F family of transcription factors, a result of which renders E2F inactive. When pRB is phosphorylated by G1 cyclin-CDK complexes it is released from E2F allowing E2F to transcriptionally activate genes. In the context of the cell cycle, E2F increases the transcription of the S-phase cyclins as well as leads to increases in its' own transcription.

Regulation of transcription factor E2F by pRB

Regulation of E2F activity by pRB. During early G1 the transcription factor E2F is inhibited by interactoin with pRB in the cytosol. Activation of the G1 cyclin-CDK complex (cyclin D-CDK4/6) results in the phosphorylation of pRB which then releases E2F. Free from pRB, E2F migrates to the nucleus where it activates the transcription of several genes including the cyclin E gene and the E2F gene itself. The autoregulation of E2F allows for high level activity of this critical cell cycle regulatory factor. In addition, the activation of cyclin E expression results in formation of active cyclin E-CDK2 complexes which keep pRB phosphorylated ensuring transit through to S-phase of the cell cycle.

One element in the growth suppressive pathway of pRB involves the MYC gene. Proliferation of keratinocytes by TGF-β is accompanied by suppression of MYC expression. The inhibition of MYC expression can be abrogated by introducing vectors that express the SV40 and adenovirus large T antigens which bind pRB. Therefore, a link exists between TGF-β, pRB and MYC expression in keratinocytes.

Transformation by the DNA tumor viruses, SV40, adeno, polyoma, human papilloma and BK is accomplished by binding of the transforming proteins of these viruses to pRB when pRB is in the hypophosphorylated (and thus the proliferation inhibitory) state.

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Wilms Tumor (WT1)

Wilms tumor is a form of nephroblastoma. This childhood cancer is the most common form of solid tumor in children with a frequency of aprroximately 1 in 10,000. In addition, Wilms tumor accounts for 8% of all childhood cancers. The cancer results from the malignant transformation of abnormally persistent renal stem cells. Several different genetic loci have been associated with the development of Wilms tumor with the most prominent being located on chromosome 11. Either one (unilateral) or both (bilateral) kidneys can be involved. Sporadic evolution of Wilms tumors is associated with chromosomal deletions, identified cytogenetically, at both 11p13 and 11p15. The 11p15 deletions may involve the IGF-2 or c-Ha-RAS loci. There are also familial forms of Wilms tumor that do not involve either locus.

The potential Wilms tumor gene at 11p13 is found in a deleted region of about 345 kb. This region contains a single transcription unit identified as WT1 that spans 50–60 kb, contains 10 exons which undergo alternative splicing resulting in the generation of at least four different WT1 mRNAs. Adding to the complexity and difficulty in assigning a function to the WT1 locus is that as a consequence of alternative splicing, alternative translational start codon useage and RNA editing, there are at least 24 different isoforms of WT1 protein. Several functional domains have been identified in each of the WT1 proteins. The differences between many of the encoded proteins is not striking but differential interactions between the WT1 proteins with distinct targets may result some level of differential control. The first hint of the potential function for WT1 came from the identification of four zinc finger domains suggesting it to be a transcription factor. Several protein forms have a three amino acid insertion (KTS) between the third and fourth zinc finger domains. Additional forms have an additional 17 amino acid sequence in exon 5 due to alternative splicing. There is a potential leucine zipper motif in the center of the protein indicating that WT1 may associate other leucine zipper containing proteins. The N-terminal 180 amino acids are involved in self-association. The WT1 proteins can act as transcriptional activators or repressors dependent upon the cellular or chromosomal context.

Several other genes or chromosomal regions have been shown to be associated with Wilms tumor and these have been identified as WT2 (chromosome 11p15.5), WT3 (chromosome 16q), WT4 (chromosome 17q12–q21), and WT5 (chromosome 7p15–p11.2). Mutations in BRCA2, glipican-3 (GPC3), and WTX (an X chromosome allele) have also been described in Wilms tumor.

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Neurofibromatosis Type 1 (NF1)

All cases of neurofibromatosis arise by inheritance of a mutant allele. Roughly 50% of all affected individuals carry new mutations which appear to arise paternally, possibly reflecting genomic imprinting. Germ line mutations at the NF1 locus result in multiple abnormal melanocytes (café-au-lait spots) and benign neurofibromas. Some patients also develop benign pheochromocytomas and CNS tumors. A small percentage of patients develop neurofibrosarcomas which are likely to be Schwann cell derived.

Assignment of the NF1 locus to chromosome 17q11.2 was done by linkage studies of affected pedigrees. The NF1 locus is extremely large as is the transcript encoded by the locus. The mRNA is 11–13 kb and contains a 7.5 kb coding region. The protein encoded is 2485 amino acids and shares striking homology to rasGAP. The NF1 protein has been given the name neurofibromin. Expression of NF1 is observed in all tissues thus far examined.

Development of benign neurofibromas versus malignant neurofibrosarcomas may be the difference between inactivation of one NF1 allele versus both alleles, respectively. However, changes other than at the NF1 locus are clearly indicated in the genesis of neurofibrosarcomas. A consistent loss of genetic material on the short arm of chromosome 17 is seen in neurofibrosarcomas but not neurofibromas. The losses at 17p affect the wild type p53 locus and may be associated with a mutant p53 allele on the other chromosome.

Characterization of the NF1 protein was carried out by generating antibodies against both fusion proteins and synthetic peptides. These antibodies specifically recognize a 220kDa protein, in both human and rat spinal cord. Neurofibromin is most abundant in the nervous system. Immunostaining of tissue sections indicates that neurons, oligodendrocytes, and non-myelinating Schwann cells contained neurofibromin, whereas astrocytes and myelinating Schwann cells do not. In schwannoma cell lines from patients with neurofibromatosis, loss of neurofibromin is associated with impaired regulation of the GTP-bound form of the proto-oncogene RAS (GTP-RAS). Analysis of other neural crest-derived tumor cell lines showed that some melanoma and neuroblastoma cell lines established from tumors occurring in patients without neurofibromatosis also contained reduced or undetectable levels of neurofibromin, with concomitant genetic abnormalities of the NF1 locus. In contrast to the schwannoma cell lines, however, GTP-RAS was appropriately regulated in the melanoma and neuroblastoma lines that were deficient in neurofibromin. These results demonstrate that some neural crest tumors not associated with neurofibromatosis have acquired somatically inactivated NF1 genes and suggested a tumor-suppressor function for neurofibromin that is independent of RAS GTPase activation.

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Familial Adenomatosis Polyposis (FAP)

Somatic mutations in the adenomatous polyposis coli (APC) gene appear to initiate colorectal cancer development in the general population, whereas it is germ line mutations that are responsible for familial adenomatous polyposis (FAP). The APC gene exhibits a dominant pattern of inheritance. Multiple colonic polyp development characterizes the disease. These polyps arise during the second and third decades of life and become malignant carcinomas and adenomas later in life. Genetic linkage analysis assigned the APC locus to 5q21. This region of the chromosome is also involved in nonfamilial forms of colon cancer. FAP adenomas appear as a result of loss-of function mutations to the APC gene. This is characteristic of tumor suppressors.

Identification of the APC gene was aided by the observation that 2 patients contained deletions at the locus spanning 100 kb of DNA. Three candidate genes in this region, DP1, SRP19 and DP2.5 were examined for mutations that could be involved in APC. The DP2.5 gene has sustained 4 distinct mutations specific to APC patients indicating this to be the APC gene. To date, more than 120 different germ line and somatic mutations have been identified in the APC gene. The vast majority of these mutations lead to C-terminal truncation of the APC protein.

The APC gene contains 15 exons spanning approximately 125 kb of DNA encoding an 8.5 kb coding region in the mRNA. Northern blotting detects an RNA of around 10 kb. An alternative form of exon 9 (9A) was also found that splices into the interior of exon 9 removing 101 amino acids from the full length APC transcript. The protein coding region of the APC gene is also extremely large encompassing 2844 amino acids. No similarities to known proteins was found except for several stretches of sequence related to intermediate filament proteins.

Using antibodies specific for the N-terminus of APC, it is possible to co-precipitate additional APC-associated proteins. One of these APC-associated proteins is β-catenin. The catenins are a family of proteins that interact with the cytoplasmic portion of the cadherins (cell-cell adhesion family of proteins), thus linking the cadherins to the actin cytoskeleton.

Catenins are equally important in the signaling cascade initiated by the Wnt family of proteins that are involved in embryonic patterning, development of the nervous system. The Wnt proteins are secreted factors that interact with cell-surface receptors. Wnt-receptor interaction induces the activity of the cytoplasmic phosphoprotein dishevelled. Activated dishevelled inhibits the serine/threonine kinase glycogen synthase kinase-3β (GSK-3β). When GSK-3β is inhibited, β-catenin becomes hypophosphorylated. The hypophosphorylated form of β-catenin migrate to the nucleus and interacts with transcription factors (in particular with T-cell factor/lymphoid enhancer-binding factor-1 (TCF/LEF-1), thereby, inducing expression of various genes. The suspected role of APC in this pathway is to bind phosphorylated β-catenin. The APC-β-catenin complex stimulates the breakdown of β-catenin. Therefore, mutations which lead to a loss of APC, or to a loss of the portion of the APC protein that interacts with β-catenin, would lead to constitutive activation of TCF/LEF-1 and unrestricted growth.

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Deleted in Colon Carcinoma (DCC)

Loss of heterozygosity (LOH) on chromosome 18 is frequently observed in colorectal carcinomas (73%) and in advanced adenomas (47%), but only occasionally in earlier-stage adenomas (11 to 13%). The area of chromosome 18 which is observed to be lost resides between 18q21.3 and the telomere. A 370 kbp stretch of DNA from the region of 18q suspected to contain the tumor suppressor gene was cloned. Expressed exons were used as probes for screening cDNA libraries to obtain clones that encoded a gene which was given the name DCC (deleted in colorectal carcinomas). A YAC contig, containing the entire DCC coding region, has been characterized showing that the DCC gene spans approximately 1.4 Mbp and contains 29 exons.

The expression of the DCC gene has been detected in most normal tissues, including colonic mucosa. Somatic mutations have been observed within the DCC gene in colorectal cancers. The types of mutations seen included a homozygous deletion of the 5' end, a point mutation within one of the introns, and 10 examples of DNA insertions within a 170 bp fragment immediately downstream of one of the exons.

Evaluation of sporadic colon cancers for allelic deletions defined an area of chromosome 18 that included two candidate tumor suppressor. One was DPC4 (see Table above) and the other was DCC. DPC4 is deleted in up to one-third of cases assayed and DCC, or a closely linked gene, was deleted in the remaining tumors. Tumor suppressor genes located on chromosome 17p and 18q are critically involved in the development of most gastric cancers. Involvement of DCC may be rather selective for gastrointestinal cancers. Loss of DCC gene expression is also an important factor in the development or progress of pancreatic adenocarcinoma.

The DCC protein is a transmembrane protein of the immunoglobulin superfamily and has structural features in common with certain types of cell-adhesion molecules, including neural-cell adhesion molecule (N-CAM). It is known that the establishment of neuronal connections requires the accurate guidance of developing axons to their targets. This guidance process involves both attractive and repulsive cues in the extracellular environment. The netrins and semaphorins are proteins that can function as diffusible attractants or repellents for developing neurons. However, the receptors and signal transduction mechanisms through which they produce their effects are poorly understood. Netrins are chemoattractants for commissural axons in the vertebral spinal cord. Recent work has shown that DCC is expressed on spinal commissural axons and possesses netrin-1-binding activity. This suggests that DCC is a receptor or a component of a receptor that mediates the effects of netrin-1 on commissural axons. Genetic evidence showing an interaction between DCC and netrin homologs in C. elegans (the UNC-40 protein) and Drosophila melanogaster (the frazzled protein) supports the role of DCC as a receptor in the axonal guidance pathway. Mice carrying a null allele of DCC harbor defects in axonal projections that are similar to those seen in netrin-1-deficient mice, further supporting the interaction between DCC and axon development. However, the DCC-deficient mice exhibited no effects on intestinal growth, differentiation or morphogenesis which fails to demonstrate a tumor-suppressor role for DCC.

DCC has been shown to induce apoptosis in the absence of ligand binding, but blocks apoptosis when engaged by netrin-1. Furthermore, DCC is a caspase substrate, and mutation of the site at which caspase-3 cleaves DCC suppresses the pro-apoptotic effect of DCC completely. DCC may function as a tumor-suppressor protein by inducing apoptosis during metastasis or tumor growth beyond the local blood supply, both of which are conditions that lack the DCC ligand. This would likely occur through functional caspase cascades leading to cleavage of DCC.

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von Hippel-Lindau Syndrome (VHL)

Like many diseases caused by loss of tumor suppressor gene activity, individuals afflicted with von Hippel-Lindau syndrome (VHL) inherit one normal copy and one mutant copy of the VHL gene. As a consequence of somatic mutation or loss of the normal VHL gene, individuals are predisposed to a wide array of tumors that include renal cell carcinomas, retinal angiomas, cerebellar hemangioblastomas and pheochromocytomas. In addition, some individuals with VHL sustain somatic alterations to both wild-type genes. This latter phenomenon is evident in the majority of sporadic clear cell renal carcinomas.

One characteristic feature of tumors from VHL patients is the high degree of vascularization, primarily as as result of the constitutive expression of the vascular endothelial growth factor (VEGF) gene. Many of the hypoxia-inducible factor (HIF) controlled genes are also constitutively expressed in these tumors whether or not high oxygen levels are present. In addition, the VHL gene has been shown to be required for cells to exit out of the cell cycle during nutrient depletion.

The role of the protein encoded by the VHL locus (pVHL) has been deduced from studies on the alterations in HIF control of hypoxia-inducible genes in VHL tumors. HIF is composed of an α-subunit and a β-subunit. The α-subunit is encoded by one of three genes (HIF1α, HIF2α, and HIF3α). The β-subunit (HIF1β) is also known as the aryl hydrocarbon receptor nuclear translocator, ARNT. Normally the HIFα subunits are degraded in the presence of oxygen due to the regulated addition of multiple ubiquitin molecules. Polyubiquitination is a key modification directing proteins for rapid degradation by the proteosome machinery. Cells lacking pVHL do not ubiquitinate HIF1α. These observations led to the identification that pVHL was a component of a ubiquitin ligase complex that is responsible for polyubinitination of HIF1α subunits.

pVHL has also been implicated in additional functions. With respect to cell cycle control, pVHL has been implicated in the downregulation of cyclin D1 which would explain why VHL tumor cells fail to exit the cell cycle on nutrient deprivation.

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Michael W King, PhD | © 1996–2013 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Last modified: August 23, 2013