The HIPPO signaling pathway is important for cell proliferation. It is regulated by the protein kinases MST1/2 and LATS1/2, and the transcriptional activators YAP and TAZ. Accordingly, the following events may be observed within a cell. A. Activation of TEADs by phosphorylated YAP/TAZ. B. Activation of YAP/TAZ on phosphorylation by MST/LATS C. Activation of TEADs by dephosphorylated YAP/TAZ D. Inactivation of MST/LATS by repressors
Which one of the following situations can support progression of cancer?
C and D
HIPPO Pathway and Cell Proliferation
The HIPPO signaling pathway is a crucial regulator of organ size and cell proliferation. It acts as a tumor suppressor pathway, preventing uncontrolled cell growth and promoting apoptosis when needed. Key components include the kinase cascade ($\text{MST1/2}$ and $\text{LATS1/2}$) and the transcriptional co-activators ($\text{YAP}$ and $\text{TAZ}$).
HIPPO Pathway Regulation
Normally, when the HIPPO pathway is active, the $\text{MST1/2}$ kinases phosphorylate and activate the $\text{LATS1/2}$ kinases. $\text{LATS1/2}$ then phosphorylate $\text{YAP}$ and $\text{TAZ}$. Phosphorylation of $\text{YAP}$ and $\text{TAZ}$ typically leads to their inactivation, often by sequestering them in the cytoplasm or marking them for degradation. In this inactive state, they cannot translocate to the nucleus and activate transcription of genes that promote cell proliferation, such as those regulated by $\text{TEAD}$ transcription factors.
Conversely, when the HIPPO pathway is inactive, $\text{YAP}$ and $\text{TAZ}$ remain dephosphorylated. In their dephosphorylated state, $\text{YAP}$ and $\text{TAZ}$ are active. They translocate to the nucleus and bind to $\text{TEAD}$ transcription factors, leading to the activation of genes that drive cell proliferation and survival. Dysregulation leading to overactivity of $\text{YAP}$ and $\text{TAZ}$ is frequently observed in cancers.
Analyzing Events Supporting Cancer Progression
Cancer progression is characterized by uncontrolled cell proliferation. Therefore, we need to identify events within the HIPPO pathway that would lead to increased cell growth. Let's evaluate the given events:
- A. Activation of $\text{TEADs}$ by phosphorylated $\text{YAP/TAZ}$.
In the standard model, phosphorylated $\text{YAP/TAZ}$ are inactive and do not activate $\text{TEADs}$. If this event were to occur, it would mean that the inhibitory phosphorylation is somehow leading to activation, which contradicts the typical pathway function but would support proliferation.
- B. Activation of $\text{YAP/TAZ}$ on phosphorylation by $\text{MST/LATS}$.
In the standard model, phosphorylation of $\text{YAP/TAZ}$ by $\text{MST/LATS}$ leads to their inactivation. This statement suggests phosphorylation causes activation, which is contrary to the established mechanism. If true, this would lead to active $\text{YAP/TAZ}$ and support proliferation, but it misrepresents the pathway.
- C. Activation of $\text{TEADs}$ by dephosphorylated $\text{YAP/TAZ}$.
This event aligns with the standard mechanism of how active $\text{YAP/TAZ}$ function. Dephosphorylated $\text{YAP/TAZ}$ are the active forms that bind to and activate $\text{TEAD}$ transcription factors, leading to the expression of pro-proliferative genes. This clearly supports cancer progression.
- D. Inactivation of $\text{MST/LATS}$ by repressors.
The $\text{MST/LATS}$ kinases are upstream inhibitors of $\text{YAP/TAZ}$ activity. If $\text{MST/LATS}$ are inactivated, they cannot phosphorylate $\text{YAP/TAZ}$. This results in an accumulation of dephosphorylated, active $\text{YAP/TAZ}$. Active $\text{YAP/TAZ}$ then promotes cell proliferation. Therefore, inactivation of $\text{MST/LATS}$ strongly supports cancer progression.
Conclusion
Events C and D both describe situations that lead to increased activity of the pro-proliferative arm of the HIPPO pathway, thereby supporting cancer progression. Event D (inactivation of $\text{MST/LATS}$) is an upstream event that causes event C (activation of $\text{TEADs}$ by dephosphorylated $\text{YAP/TAZ}$). Therefore, the combination of C and D represents conditions that would promote uncontrolled cell growth.
Important Questions from Cell Division and Cell Cycle
During cell cycle, entry in the S-phase is tightly regulated. This is possible because:
A. APC/C promotes ubiquitination of S-phase cyclins and mitotic cyclins, marking them for proteolyses at the mitotic exit.
B. Cyclin B1 helps in the activation of S-phase CDKs only in late G1.
C. As mitotic CDK activity declines in late mitosis, cdc14 phosphatase activates APC/C by dephosphorylating Cdh1, thus promoting formation of APC/CCdh1
D. Securin keeps S-phase cyclins in inactive state till late G1.
Which one of the options represents all correct statements?
Following statements were made about cell cycle regulation:
A. De novo synthesis and destruction of Cyclin B are essential for cell cycle progression in yeast.
B. De novo synthesis and destruction of Cyclin B and the related Cyclin dependent Kinase (CDK) are essential for cell cycle progression.
C. CDK activity is regulated by both activating and inhibitory phosphorylation.
D. Retinoblastoma (Rb) functions as an inhibitor of G2 to M transition.
E. Inactivation of Sic 1 is essential for transition into S phase.
Which one of the following represents the combination of the correct statements?
The table below lists cell cycle regulatory proteins and their known functions
Which one of the following options represents the correct match between cell cycle regulatory proteins with their known functions?Cell Cycle regu latory proteins Function A Cdk-activating kinase (CAK) (i) Suppresses G1/S-Cdk and S-Cdk activation in G1; helps cells withdraw from cell cycle when they terminally differentiate; phosphorylation by Cdk2 triggers its ubiquitylation by SCF. B Wee1 kinase (ii) Suppresses G1/S-Cdk and S-Cdk activities following DNA damage C p27 (mammals) (iii) Phosphorylates inhibitory sites in Cdks: primarily involved in suppressing Cdk1 activity before mitosis D p21 (mammals) (iv) Phosphorylates an activating site in Cdks Following statements were made about the characteristics of cyclin proteins:
A. Synthesis of M-cyclin is dependent on the cyclin mRNA that is newly transcribed after every cycle.
B. Destruction of M-cyclin toward the end of mitosis is driven by ubiquitin independent proteolytic system.
C. G1 cyclins can be activated by mitogenic factors.
D. Retinoblastoma (Rb) is a key target of the activated cyclin D - Cdk 4/6 complex.
E. While cyclin A1 expression is ubiquitous, cyclin A2 expression is restricted to the germ cell lineages.
Which one of the following options contains a combination of all correct statements?
To test the impact of cAMP on protein kinase A conformation in cells, an investigator made FRET biosensor by fusing two fluorescent proteins at the N-and C-terminus of protein kinase A. In the absence of cAMP in the cellular milieu, no FRET signal was detected. However, upon cAMP addition, a strong emission at 530 nm was observed. What could be the best configuration of fluorophores that were used by the investigator?
