Question

For each of the situations listed, provide a plausible explanation for how it could lead to unrestricted cell division. a. Colon cancer cells often contain mutations in the gene encoding the prostaglandin \(\mathrm{E}_{2}\) receptor. \(\mathrm{PGE}_{2}\) is a growth factor required for the division of cells in the gastrointestinal tract. b. Kaposi sarcoma, a common tumor in people with untreated AIDS, is caused by a virus carrying a gene for a protein similar to the chemokine receptors CXCR1 and CXCR2. Chemokines are cell-specific growth factors. c. Adenovirus, a tumor virus, carries a gene for the protein E1A, which binds to the retinoblastoma protein, pRb. (Hint: See Fig, 12-40.) d. An important feature of many oncogenes and tumor suppressor genes is their cell-type specificity. For example, mutations in the \(\mathrm{PGE}_{2}\) receptor are not typically found in lung tumors. Explain this observation. (Note that \(\mathrm{PGE}_{2}\) acts through a GPCR in the plasma membrane.)

Short answer

Mutations in growth factor receptors or related pathways can cause uncontrolled cell division specific to certain cell types, reflecting tissue-specific receptor expression and signaling.

Step-by-step solution

Understand Colon Cancer and PGE2

A mutation in the gene encoding the prostaglandin E2 (PGE2) receptor in colon cancer cells can disrupt normal growth regulation. Normally, PGE2, acting as a growth factor, binds to its receptor and regulates cell division in the gastrointestinal tract. A mutation in the receptor may cause it to become constitutively active or negative, resulting in uncontrolled cell division, characteristic of cancer.

Explain Kaposi Sarcoma and Viral Protein

Kaposi sarcoma is linked to a virus that carries a gene coding for a protein similar to chemokine receptors CXCR1 and CXCR2. Chemokines promote cell-specific growth, and the viral protein may mimic these receptors, leading to continuous activation and growth-promoting pathways even in the absence of actual chemokines. This leads to unchecked cell proliferation.

Examine Adenovirus and the E1A Protein

Adenovirus encodes the E1A protein, which binds to the retinoblastoma protein (pRb). Normally, pRb regulates the cell cycle by controlling the transition from the G1 to S phase. When E1A binds to pRb, it disrupts this regulation, preventing pRb from controlling the cell cycle, resulting in uncontrolled cell proliferation.

Discuss Cell-Type Specificity of Mutations

The cell-type specificity of oncogenes and tumor suppressor genes is often due to the expression patterns of growth factor receptors. The PGE2 receptor's involvement in colon but not lung cancer suggests its role is specific to the gastrointestinal tract where PGE2 acts via GPCRs. Different tissues express diverse receptors, influencing where mutations will affect growth control.

Key concepts

Oncogenes

Oncogenes are genes that, when mutated or expressed at high levels, can drive unrestricted cell division and lead to cancer. These genes are like a car's gas pedal stuck to the floor—pushing the cell to divide uncontrollably. Often, oncogenes are derived from normal genes called proto-oncogenes that play a role in regular cell growth and division.

When proto-oncogenes mutate, they can become permanently activated as oncogenes. For instance, if a gene that codes for a receptor on a cell surface becomes an oncogene, it might continuously tell the cell to grow, even in the absence of signals. This relentless signal can transform normal cells into cancerous ones. Oncogenes can arise in various ways, such as duplication, where there are too many copies, or mutation, where the gene's information changes.

Understanding how oncogenes work helps us know why specific cancers develop and how they might be treated. Developing treatments that can target these constantly active signals is crucial for effective cancer therapy.

Tumor Suppressor Genes

Tumor suppressor genes act as a cell's brakes, preventing uncontrolled cell growth. These genes help repair DNA, control cell division, or cause cells to undergo apoptosis (cell death) when they are damaged. Common tumor suppressor genes include p53 and RB1.

Mutations or deletions in these genes can remove the brakes, allowing for uncontrolled cell growth, similar to a car speeding downhill when its brakes fail. For example, the retinoblastoma protein (pRb) is a crucial tumor suppressor that regulates the cell's progression from G1 to S phase in the cell cycle. It ensures that the cell only moves forward when conditions are ideal. If a virus, such as adenovirus, produces a protein like E1A that binds and inactivates pRb, the regulation is lost, and cells can divide uncontrollably.

• By losing tumor suppressor gene function, cells lose key regulatory checkpoints.
• Without these checkpoints, errors in DNA or cell division can lead to cancer.

Restoring the function of these genes or compensating for their loss is a focus in cancer research.

Growth Factors

Growth factors are proteins or molecules that signal cells to divide and grow. They are very important for regulating normal bodily functions. Imagine these factors as coaches that tell the cells when it's time to grow, divide, or even stop growing.

Prostaglandin E2 (PGE2) is an example that acts as a growth factor in the gastrointestinal tract. It binds to specific receptors on cells, signaling them to divide and grow appropriately. However, if a mutation occurs in the receptor that PGE2 binds to, it may continuously signal for division, leading to cancer.

Growth factors are crucial during development and tissue repair. However, their pathways can sometimes be hijacked by cancer cells to ensure their own proliferation. Understanding how growth factors work and are manipulated by cancer cells helps in designing therapies that can block these signals, keeping cell growth in check.

Cancer Cell Signaling

Cancer cell signaling involves how cells communicate through chemical signals to regulate growth and survival. This communication often goes haywire in cancer. Cells use proteins, receptors, and complex pathways to send and receive signals about their environment.

Consider cancer cell signaling like a misbehaving team, where some members take over without following the rules. This communication breakdown can lead to abnormal and excessive cell growth. In cancers, like colon cancer or Kaposi sarcoma, mutations in genes related to signaling pathways can cause these signals to be "stuck" in the activate or proliferate positions.

Finger pointing is a classic example—the gene mutations lead to malfunctioning signaling pathways that encourage cell growth even in unfavorable conditions, contributing to tumor development.

• Faulty signaling causes cells to ignore stop signals or create their own grow signals.
• This can lead to increased survival, proliferation, and even spread of cancer cells.

Targeting these pathways with drugs can help restore balance to cell behavior and provide effective treatments.