Do mutated c-sis oncogenes only affect cell growth?

Do mutated c-sis oncogenes only affect cell growth?

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Since c-sis regulates only cell growth, a mutation there should only lead to an out of control growth of the cell, but the cells would still be mature, since c-sis does not regulate the function or maturing of the cell.

However a mutation in c-sis leads to cancer, and cancer is not just cells that grow out of control, but also don't performe their function (are not mature). Can someone explain how a c-sis mutation still leads to cancer please?

Cancer is not a disease like the flu or E. bola, where there is a single quick and easy cause for the disease which you can locate and describe in a single sentence. Cancer consists of malignant cell growth, it is true, but why are the cells growing out of control?

The fact is that there is not one single cause. At some point along the way, some cell experience a mutation to some gene which resulted in a slightly higher rate of proliferation than normal. However, this in and of itself is not even enough to produce a tumour. It simply gives the cells a higher number of daughter cells, and consequently, a higher risk of having more mutations.

At some point, one of those daughter cells acquires a mutation which results in higher levels yet of proliferation, or a mutation which encourages angiogenesis, or (in the case of epithelial cells, for instance) a mutation which allows the cell to escape typical anoikis pathways and perhaps perforate its basement membrane without dying.

Even the process of metastasis requires multiple mutations to happen, and yet if a tumour does not metastasize, it is typically regarded as benign. The point is, cancer is not caused by a single mutation to an oncogene or otherwise. It is caused by an accumulation of mutations which permit the cells to proliferate much faster than normal, to recruit the body's resources, and to live in tissues all around the body.

In the case of the particular gene that you mentioned, the exact role of the c-sis oncogene in cancer prevention is still unclear; in fact, according to the OMIM page,

The protein product of the c-sis gene has not been identified.

… though the gene is very similar to platelet derived growth factor genes, some of which have been identified as mitogenic factors. Theoretically, therefore, it is possible that a mutation to the c-sis results in excessive mitogenic stimulation, resulting in an increase in cell division and proliferation. But that last sentence is speculation, not hard science.


We don't know, but it's possible c-sis encourages faster cell division.


  • Platelet-derived growth factor, beta polypeptide; PDGFB on
  • Josephs SF, Guo C, Ratner L, Wong-Staal F. 1984. Human-proto-oncogene nucleotide sequences corresponding to the transforming region of simian sarcoma virus. Science 223(4635): 487-491.

Mutated skin stem cells self-correct to prevent cancer

Widespread mutations in a cancer-driving gene drive excess growth in mouse skin (left). This is blocked when a specific regulator of protein production is turned on at high levels (right). The white and red stain different types of keratin fibers in mouse skin. Image courtesy of the Beronja Lab

Certain inherited genetic mutations are well known to increase a person’s risk of developing cancer. But not every person who inherits a powerful cancer-predisposing mutation will get cancer, and among those who do, only a few cells turn into tumors. Why?

In new work published June 8 in Cell Stem Cell, scientists at Fred Hutchinson Cancer Research Center discovered a previously unknown self-correcting mechanism by which skin tissue carrying widespread cancer-causing mutations resists tumor growth in mice. Inherited mutations in the Ras family of genes cause a group of disorders called RASopathies and are often mutated in human tumors. The team examined why these mutations raise the risk of cancer — but don’t guarantee it.

“The findings help answer the mystery of why people who have congenital syndromes driven by activating mutations in powerful oncogenes [cancer-driving genes] are only slightly predisposed to get cancer,” said Dr. Slobodan Beronja, who led the project and studies skin stem cells and how tumors can co-opt some of their functions.

He and then-graduate student Dr. Elise Cai, who spearheaded the work, found that when skin stem cells share a cancer-driving mutation, they multiply more — but balance this overgrowth by reducing the rate at which they renew themselves.

Unexpectedly, the skin stem cells do this by fine-tuning production (also known as translation) of specific proteins, rather than changing which genes they turn on.

Because cancer cells often thrive by shifting the balance of normal cellular processes, including co-opting stem cells’ ability to self-renew, the findings could be a step toward therapeutic strategies designed to shift these processes back to normal in cancer cells, said Beronja — and suggests that drugs that target general cellular processes like protein production should be developed with caution.

How does the skin deal with widespread mutations?

Our skin is in a constant state of renewal. As old skin cells slough off, they are continually replaced by new skin cells, produced by skin stem cells in the tissue’s deepest layers. Skin stem cells balance this function with renewal, replacing themselves in order to maintain a pool of cells capable of producing more skin tissue in the future. At each division, skin stem cells can produce two specialized skin cells, two skin stem cells, or one of each. Striking the right balance between the choices ensures that both stem cell renewal and skin cell replacement continue.

In previous work, Beronja and postdoctoral fellow Dr. Zhe Ying showed that when a skin stem cell harbors a cancer-driving mutation, it becomes more likely to generate two specialized skin cells when it divides. Over time, the mutated skin stem cell fails to renew itself and turns into cells that eventually slough off, allowing the skin to expel mutated cells as needed. The healthy surrounding skin stem cells pick up the slack and continue maintaining the tissue.

This strategy explains how skin can deal with DNA damage acquired over time. But sometimes an oncogenic mutation, one that increases cancer risk, is inherited from a parent, which means it’s found in the DNA of every cell in a person’s body.

“In this case, you don't have wild-type [healthy] cells to go in and replace these … because everything is oncogenic,” Beronja said.

But again, in these situations, not every cell turns into cancer, and not every carrier will develop a tumor. Beronja wanted to figure out why.

Dr. Slobodan Beronja Photo by Robert Hood / Fred Hutch News Service

Skin stem cells reduce their renewal rate in response to cancer-driving mutations

Former graduate student Cai, a postdoctoral medical scientist in training, took on the challenge. She focused on learning how skin tissue handles widespread mutations in a gene called H-Ras, which is mutated in Costello syndrome, an inherited disorder that affects many systems of the body and increases cancer risk.

The Ras gene family controls cell growth. Many human tumors contain mutations that spur cell growth by making a Ras family member permanently active. One study found that having a RASopathy raised the risk of childhood cancer by 10-fold. (On average, the risk of developing cancer in childhood is 0.33%, or 1 in 300.)

Cai chose to examine the effect of permanently activating H-Ras in every cell of the body, mimicking inherited mutations found in people with Costello syndrome. She genetically modified mice so that all the cells in their skin turned on a mutated form of H-Ras, which is associated with cancer in humans.

Cai found that though there were signs of skin cell overgrowth, or proliferation, in mutant mice, the animals did not form tumors, and the excess growth was less than she and her colleagues had expected. After ruling out other ways the cells might have reined in their growth, she measured the stem cell renewal rate. Cai found that stem cells with active H-Ras had significantly turned down their renewal rate, suggesting that they had shifted to producing more skin cells but replacing stem cells less often.

“This increase in proliferation seems to be balanced by reduced renewal, but still renewal that ensures long-term maintenance [of the skin tissue],” Beronja said. “So it's a qualitatively different result that basically ensures that tissues in these people don't collapse and are actually maintained.”

Protein production fine tunes stem cell renewal

Cai next wanted to determine the cellular process skin stem cells use to ramp down their renewal rate. Work from other scientists gave her a clue. Other labs had shown that a cellular process called translation was linked to renewal and proliferation: more translation correlated with increased cell growth and division and reduced renewal.

Translation is a key step in the system our cells use to make the information encoded in our genes tangible. Our DNA encodes the proteins that make all of our cellular processes possible, but it takes a few steps to get from DNA to protein. First cells copy the information in DNA into a new form, creating molecules called messenger RNA, or mRNA, which cellular protein-making factories use as the instruction for building proteins. They read, or translate, these mRNAs into proteins. Cells can fine tune how much genes are turned on by changing how and when translation occurs.

Cai measured the translation rate in skin stem cells to see if it changed in response to the presence of mutated Ras. She found that the translation rate in skin stem cells from mutant mice was higher than in skin stem cells in normal mice. Reducing H-Ras activity also reduced the translation rate in mutant skin stem cells.

She screened genes known to be involved in translation to see if any influenced skin stem cells’ proliferation or renewal rate when H-Ras was permanently active. Out of the 200 genes whose effects Cai examined, one stood out: eif2b5. This gene is part of the molecular complex that initiates the translation of mRNA to protein. When Cai suppressed mutant cells’ ability to make eif2b5 protein, their translation rate dropped. This didn’t change the translation rate in normal cells.

Cai found that eif2b5 also appeared to be causing the increased growth and decreased renewal seen in H-Ras-mutant skin stem cells. When she genetically manipulated mice with mutant H-Ras to reduce eif2b5 levels in their skin stem cells, this reduced proliferation and increased renewal. Again, changing eif2b5 levels in healthy mice did not affect the renewal rate or growth rate of their skin stem cells.

We were totally surprised,” Beronja said, “Because again, when you think translation, you think a general process — this suggests that there's some specificity.”

And, he noted, If you knock down eif2b5, it reverts, basically, to wild-type tissue. [The knockdown] completely fixes it, and there’s no effect in the wild-type background.”

Cell’s protein-recycling system involved in control of stem cell renewal

Working with Hutch translation expert Dr. Andrew Hsieh, Cai discovered that overactive H-Ras only ramped up translation of a subset of mRNAs. About 40% of these were specifically controlled by eif2b5. Together with members of the Hsieh Lab, they found that these mRNAs have a characteristic sequence that attracts molecular complexes containing eif2b5, ensuring specific, rather than general, control.

Surprisingly, Cai found that in skin stem cells with overactive H-Ras, eif2b5 reduced the cells’ ability to self-renew by increasing translation of genes that direct proteins to the cells’ protein-recycling system, in which proteins are degraded and their components reused.

She and Beronja had expected that skin stem cells would regulate their “stemness” by changing the levels of proteins whose job it is to turn genes on. But turning genes on takes time. By drawing on the protein-recycling system, skin stem cells may be able to quickly remove renewal-promoting proteins from circulation.

When Cai blocked this process in mice with mutated H-Ras, she found that they formed skin tumors more quickly than mice whose skin stem cells were allowed to handle mutated H-Ras normally. After about 30 days, half the mice with mutated H-Ras and reduced cellular protein recycling had developed tumors it took nearly 50 days for half the mice with only mutated H-Ras to develop tumors. In contrast, enhancing protein recycling in mice with mutated H-Ras further extended the time they lived without developing tumors.

Understanding the system

Beronja’s main concern now is to uncover the mechanism by which the protein-recycling system controls skin stem cell renewal. Presumably the cells are using the system to break down specific stem cell factors, but they remain to be discovered.

Beronja also thinks that the findings could help explain more about how cancer develops generally. Age is one of the biggest risk factors for cancer this is generally attributed to the fact that as we age, we accumulate more mutations. But perhaps this self-correcting ability to “tolerate” oncogenic mutations fades with time?

“It's quite possible that ability to handle [cancer-driving mutations] eventually goes away. And it could be one of the explanations of why cancer is a disease of older people,” he said.

Beronja didn’t expect to find that translation could slow tumor growth. The conventional scientific wisdom has been that translation usually helps drive cancer: Tumor cells need proteins to grow, and to make proteins they need to increase production.

“In this case, we actually showed that increased translation is tumor-suppressive,” Beronja said.

This highlights a potential drawback to therapeutic strategies that aim to halt tumor growth by restricting translation, he said. As drugs to inhibit translation are increasingly being explored as anti-cancer agents, Beronja hopes scientists bear in mind that broad changes in translation could have unintended, and possibly negative, consequences for cancer growth.

“I think it’s a cautionary tale,” he said. “Basically, don’t target something you don’t understand.”

The National Institute of Arthritis and Muskuloskeletal and Skin Diseases and the National Cancer Institute funded this work.

The Cell: A Molecular Approach. 2nd edition.

The activation of cellular oncogenes represents only one of two distinct types of genetic alterations involved in tumor development the other is inactivation of tumor suppressor genes. Oncogenes drive abnormal cell proliferation as a consequence of genetic alterations that either increase gene expression or lead to uncontrolled activity of the oncogene-encoded proteins. Tumor suppressor genes represent the opposite side of cell growth control, normally acting to inhibit cell proliferation and tumor development. In many tumors, these genes are lost or inactivated, thereby removing negative regulators of cell proliferation and contributing to the abnormal proliferation of tumor cells.


The jun Oncoge

The jun gene was originally identified as the oncogenic element of the avian sarcoma virus 17, a retrovirus that readily causes fibrosarcomas in chickens (ASV17 ‘jun’ is a truncated form of ju-nana, Japanese for 17). This viral jun (v-jun) is derived from the genome of the avian host and inserted into the retroviral genome as a result of recombination between virus and cell. The N-terminus of the v-Jun protein is joined to viral sequences, and in the infected cell v-Jun is expressed as a hybrid Gag–Jun fusion protein ( Figure 1 ). Besides being fused to Gag, the v-Jun protein differs from the cellular c-Jun protein by (1) the N-terminal addition of nine amino acids encoded by the 5′ untranslated region of c-Jun, (2) an internal deletion of 27 amino acids defining the delta domain (δ), and (3) two point mutations, altering serine 222 to phenylalanine and cysteine 248 to serine. These structural distinctions of v-Jun and its high expression level that is controlled by the active retroviral promoter are the underlying cause for the potent tumorigenicity of v-Jun.

Figure 1 . The primary structure of the chicken c-Jun and v-Jun proteins. Positions of amino acids are shown in the figure. Red bars indicate structural differences between c-Jun and v-Jun. Various protein domains are color-coded: yellow: bZIP, basic region and leucine zipper blue: transactivation domains A1 and A2 dark gray: nine additional amino acids encoded by the 5′ untranslated region of chicken c-jun green: ASV17 viral Gag protein sequences.


65 How are protooncogenes activated to become oncogenes?

Protooncogenes can be transformed into oncogenes through four basic mechanisms:

Point mutation: A single base substitution in the DNA chain results in a miscoded protein. Point mutation of the ras oncogene is found in approximately 30% of common human cancers, such as carcinoma of the lung, large intestine, and pancreas.

Gene amplification: This lesion is associated with an increased number of copies of a protooncogene. The best example is amplification of c-myc in neuroblastomas. The more c-myc is amplified, the more malignant are these childhood tumors.

Chromosomal rearrangements: Translocations and deletions of parts of chromosomes lead to a juxtaposition of genes that are normally not in close proximity to one another. These rearrangements form new gene complexes, in which one gene acts as the promoter for the other. For example, translocation of the c-myc gene (normally located on chromosome 8) onto chromosome 14 positions this protooncogene next to the immunoglobulin heavy chain gene. The immunoglobulin gene is activated in B lymphocytes and acts as a promoter for the c-myc gene. This chromosomal rearrangement is the basis of malignant transformation of lymphocytes in Burkitt lymphoma.

Insertional mutagenesis: This form of oncogene activation occurs because of an insertion of a viral gene into the mammalian DNA, resulting in genetic dysregulation. The best example of such an event may be found in hepatitis virus B–infected human liver cells.


The genes that code for the positive cell cycle regulators are called proto-oncogenes. Proto-oncogenes are normal genes that, when mutated in certain ways, become oncogenes, genes that cause a cell to become cancerous. Consider what might happen to the cell cycle in a cell with a recently acquired oncogene. In most instances, the alteration of the DNA sequence will result in a less functional (or non-functional) protein. The result is detrimental to the cell and will likely prevent the cell from completing the cell cycle however, the organism is not harmed because the mutation will not be carried forward. If a cell cannot reproduce, the mutation is not propagated and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator. For example, a mutation that allows Cdk to be activated without being partnered with cyclin could push the cell cycle past a checkpoint before all of the required conditions are met. If the resulting daughter cells are too damaged to undergo further cell divisions, the mutation would not be propagated and no harm would come to the organism. However, if the atypical daughter cells are able to undergo further cell divisions, subsequent generations of cells will probably accumulate even more mutations, some possibly in additional genes that regulate the cell cycle.

The Cdk gene in the above example is only one of many genes that are considered proto-oncogenes. In addition to the cell cycle regulatory proteins, any protein that influences the cycle can be altered in such a way as to override cell cycle checkpoints. An oncogene is any gene that, when altered, leads to an increase in the rate of cell cycle progression.

Gene variants

People can also have different versions of genes that are not mutations. Common differences in genes are called variants. These versions are inherited and are present in every cell of the body. The most common type of gene variant involves a change in only one base (nucleotide) of a gene. These are called single nucleotide polymorphisms (SNPs, pronounced “snips”). There are estimated to be millions of SNPs in each person’s DNA.

Other types of variants are less common. Many genes contain sequences of bases that are repeated over and over. A common type of variant involves a change in the number of these repeats.

Some variants have no apparent effect on the function of the gene. Others tend to influence the function of genes in a subtle way, such as making them slightly more or less active. These changes don’t cause cancer directly, but can make someone more likely to get cancer by affecting things like hormone levels and metabolism. For example, some gene variants affect levels of estrogen and progesterone, which can affect the risk of breast and endometrial cancers. Others can affect the breakdown of toxins in cigarette smoke, making a person more likely to get lung and other cancers.

Gene variants can also play a role in diseases that impact cancer risk – like diabetes and obesity.

Variants and low-penetrance mutations can be similar. The main difference between the two is how common they are. Mutations are rare, while gene variants are more common.

Still, since these variants are common and someone can have many of them, their effect can add up. Studies have shown that these variants can influence cancer risk and, together with low penetrance mutations, they may account for a large part of the cancer risk that runs in families.

  • A direct oncogenic viral mechanism involves either the insertion of additional viral oncogenic genes into the host cell, or the enhancement of already existing oncogenic genes in the genome.
  • Tumor viruses come in a variety of forms. Viruses with a DNA genome, such as adenovirus, and viruses with an RNA genome, like the Hepatitis C virus (HCV), can cause cancers. Retroviruses having both DNA and RNA genomes (Human T-lymphotropic virus and hepatitis B virus) can also cause cancers.
  • Viruses can become carcinogenic when they integrate into the host cell genome as part of a biological accident, such as polyomaviruses and papillomaviruses.

Worldwide, cancer viruses are estimated to cause 15-20% of all cancers in humans. Most viral infections, however, do not lead to tumor formation several factors influence the progression from viral infection to cancer development. These factors include host&rsquos genetic makeup, mutation occurrence, exposure to cancer causing agents, and immune impairment.

Cancer cells have characteristics that differ from normal cells, such as acquiring the ability to grow uncontrollably. This can result from having control of their own growth signals, losing sensitivity to anti-growth signals, and losing the ability to undergo apoptosis, or programmed cell death. The human genome contains a variety of genes which normally control the growth and replication of cells. It is important for cells to replicate only when needed (such as to replace dead cells) and that those cells which replicate have a correctly copied genome with no mutations. One set of genes in human cells, called proto-oncogenes, produces proteins which respond to environmental and intercellular signals and determine whether or not a cell should replicate. When a proto-oncogene is mutated (into what is now called an oncogene) it can tell the cell to replicate even when it shouldn't. This results in uncontrolled cell growth. The other important part of this growth control is to only allow cells with no errors in their genome to replicate. This is the job of proteins called tumor suppressors. One of the most critical tumor suppressors is a protein called p53. Normally, tumor suppressors will force a cell to apoptosis (programmed cell death) if the DNA of the cell is damaged. In cancer, however, tumor suppressors are disabled (either by the gene being damaged or the protein being inactivated), thus allowing mutated cells to replicate. The development of cancer usually involves both oncogenes and the disabling of tumor suppressors (Fig.

Oncogenesis (the start of cancer) can occur when a virus infects and genetically alters a cell. Scientists have been able to discern some commonality among viruses that cause tumors. The tumor viruses (or oncoviruses) change cells by integrating their genetic material with the host cell&rsquos DNA. Unlike the integration seen in prophages, this is a permanent insertion the genetic material is never removed. The inserted viral DNA could either affect the functioning of a proto-oncogene (resulting in an oncogene and uncontrolled cell growth) or disable a tumor suppressor (resulting in the growth of cells with damaged DNA). In some cases the virus itself carries genes which can impair the proper control of cell growth.

Figure Mutations Leading to Increased Cell Division: Cancer is caused by a series of mutations. Viral infections contribute to the process through genetic alteration.

The insertion mechanism can differ depending on whether the nucleic acid in the virus is DNA or RNA. In DNA viruses, the genetic material can be directly inserted into the host&rsquos DNA. RNA viruses must first transcribe RNA to DNA and then insert the genetic material into the host cell&rsquos DNA.

Inheritance and Oncogenes vs. Tumor Suppressor Genes

Several important differences exist between oncogenes and tumor suppressor genes in cancer.

In general, oncogenes are dominant. In our bodies, we have two sets of each of our chromosomes and two sets of genes: one from each of our parents. With dominant genes, only one of the two copies needs to be mutated or abnormal for a negative effect to occur.

Take, for example, brown eyes. If people inherit one copy of the brown-eyed gene and one copy of the blue-eyed gene, their eye color will always be brown. In the car analogy, it takes only one copy of a mutated gene controlling the accelerator for the car to run out of control (only one of the two proto-oncogenes needs to be mutated to become an oncogene).

Tumor suppressor genes, in contrast, tend to be recessive. That is, just like you need two genes for blue eyes in order to have blue-eyes, two suppressor genes must both be damaged in order to contribute to cancer.

It's important to note that the relation between oncogenes and tumor suppressor genes is much more complex than this, and the two are often intertwined. For example, a mutation in a suppressor gene may result in proteins that are unable to repair mutations in an oncogene, and this interaction drives the process forward.

Health Conditions Related to Genetic Changes

Noonan syndrome

More than 25 mutations causing Noonan syndrome have been identified in the RAF1 gene. Noonan syndrome is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. The RAF1 gene mutations change single protein building blocks (amino acids) in the RAF1 protein. These changes increase protein activity and disrupt the regulation of the RAS/MAPK signaling pathway causing problems with cell division, apoptosis, cell differentiation, and cell migration. Researchers believe that this disruption in normal cell processes plays a role in the signs and symptoms of Noonan syndrome, specifically cardiac abnormalities. It has been noted that people with Noonan syndrome caused by a RAF1 gene mutation have a greater incidence of heart defects than other people with Noonan syndrome, specifically a condition called hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood.

Noonan syndrome with multiple lentigines

At least two mutations in the RAF1 gene have been found to cause Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome). This condition is characterized by multiple brown skin spots (lentigines), heart defects, short stature, a sunken or protruding chest, and distinctive facial features. The RAF1 gene mutations change single amino acids in the RAF1 protein: One mutation replaces the amino acid serine with the amino acid leucine at position 257 (written Ser257Leu or S257L) and the other mutation replaces the amino acid leucine with the amino acid valine at position 613 (written Leu613Val or L613V).

The RAF1 gene changes that cause Noonan syndrome with multiple lentigines are believed to abnormally activate the RAF1 protein, which disrupts the regulation of the RAS/MAPK signaling pathway that controls cell functions such as growth and division. This misregulation can result in the various features of Noonan syndrome with multiple lentigines.

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Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the RAF1 gene are involved in the development of several types of cancer. These mutations lead to a RAF1 protein that is always active and can direct cells to grow and divide uncontrollably. Studies suggest that RAF1 gene mutations may be found in ovarian, lung, and colorectal cancers. Somatic mutations in the RAF1 gene are a rare cause of cancer.

For reasons that are unclear, inherited mutations in the RAF1 gene do not appear to increase the risk of cancer in people with Noonan syndrome with multiple lentigines or Noonan syndrome.