hello everybody and welcome to the med a USM step one Essentials video series where we talk about very high yield step one topics in this video we will be talking about a topic which shows up very frequently on the exam that topic is the cell cycle and the proteins involved in regulating it namely cyclin retinol blastoma protein or RB mp53 as we will soon learn the genes which code the these proteins are known as tumor suppressor genes and they are extremely important because they are associated with the development of Cancer all right so let's get started the cell cycle can be broken down to two major phases inase and mitosis interface and mitosis can be further broken down to various subphases as well an easy way to conceptualize and memorize the cell cycle is to picture a new cell which has just freshly divided from a parent cell this cell will start off here right after mitosis because mitosis is essentially the part of the cell cycle in which the cell physically divides if the cell starts right after mitosis then it must start off in the G1 phase which is the first phase of interphase as the cell matures it will eventually go through the S phase and then the G2 phase the S phase always occurs before the G2 phase we will talk about why shortly lastly mitosis occurs after the G2 phase during mitosis the cell essentially physically splits to form two new identical cells it is not as worthwhile to memorize the sequence of the phases of mitosis as it is to know what is exactly happening in each phase another worthwhile thing to understand is that before a cell progresses to a new phase in the cell cycle certain conditions must be met these conditions can be thought as quality control requirements the process by which this happens is often referred to as cell cycle checkpoints and we will talk about them in just a minute for now let's talk about mitosis as we have already mentioned mitosis is the part of the cell cycle in which the nucleus and cytoplasm of a parent cell splits into two genetically identical cells known as daughter cells the Reon reason it is important to know that the daughter's cells are genetically identical to each other and the parent cell is because there is another type of cell division in which this is not the case this type of cell division is known as meosis and it is the type of cell division which occurs in germ cells which is another name for sperm and US sites so remember in mitosis the daughter cells are always genetically identical and in meiosis they are not errors in mitosis can lead to one of three consequences it can lead to inhibition of cell division and therefore the cell cycle this is the principle behind the anti-neoplastic drugs such as pxel and Vin blastin these drugs create errors and mitosis which cause the entire cell cycle to stop and therefore the growth of the tumor errors and mitosis can also lead to cell death which explains why these drugs can also kill cancer cells lastly errors and mitosis can lead to genetic mutations such as anlo which is when the cell has an incorrect number of chromosomes okay so let's briefly go over the individual steps of mitosis the first phase of mitosis is known as prophase the principal thing that happens during prophase is that the nuclear envelope breaks down and chromatine begins to condense in order to form chromosomes the next phase is called a metaphase several things occur in metaphase first the chromatine condenses even more to form full chromosomes next the chromosomes align at the center of the cell and microtubules attach from the chromosomes to the centrosome which are located in the poles of the cell the next phase is called the anaphase during anaphase the chromosomes are pulled to the opposite poles of the cell by the action of microtubules it is important to recognize that metaphase and anaphase are the phases of mitosis which the antineoplastics such as pxel and Vin blastin exert their effect these drugs work worked by inhibiting the action of microtubules which are essential for mitosis progression the last phase of mitosis is called telophase in this phase the chromosomes begin to decondense back to chromatine and the nuclear envelope reforms while these are all important things to know regarding mitosis perhaps the most important thing to know about mitosis in regards to the cell cycle is that once mitosis has occurred any DNA changes or mutations which occurred during replication cannot be corrected in other words the DNA mutations become permanent for this reason mitosis can be thought as an end point in the steps of the cell cycle because once mitosis is complete there is nothing else that can be done to ensure that DNA mutations can be repaired throughout the cell cycle there are numerous complex quality control checkpoints which ensure that mitosis occurs only when the cell is free of DNA mutations the culmination of all of these checkpoints and complex molecular mechanisms is to ensure that no DNA mutations have occurred during the process of DNA replication okay so now let's talk about the other major components of the cell cycle interphase interphase is the part of the cell cycle in which the cell grows replicates its DNA and synthesizes new proteins in preparation for mitosis cells which are constantly dividing such as bone marrow cells gut epithelium skin and hair follicles spend a short period of time in interphase while cells which do not divide such as neurons and muscle cells are permanently stuck in interphase neurons and muscle cells which do not divide are said to be in a stage of interphase known as g0 so just like mitosis interface is composed of several phases as we said before it is useful to think as the G1 phase as the first phase of the cell cycle since this is the phase that occurs right after a pair of new cells have formed Following mitosis during the G1 or growth Phase 1 the cell grows makes new organel and synthesizes proteins required for DNA replication during this phase the cell is preparing for DNA replication during the S phase or synthesis phase the cell's DNA is replicated during the G2 or growth Phase 2 the cell begins to synthesize the proteins required for mitosis in preparation for cell division lastly cells in the g0 phase are not preparing for application but instead are in a resting state this is also known as the resting phase cells which enter the g0 phase may stay permanently in the g0 phase or may enter the cell cycle and undergo mitosis now that we understand the steps of interface and mitosis let's talk about the cell cycle checkpoints these checkpoints are extremely important and relevant because dysfunction of these checkpoints is believed to be one of the major mechanisms by which cancer occurs throughout the cell cycle there are various quality control checkpoints which function to ensure that various cellular conditions are met before proceeding with the cell cycle and ultimately cell division one of the conditions which these checkpoints checks is that no DNA errors are present which can potentially be passed down to the Future daughter cells remember once mitosis has occurred there is no way to repair any potential DNA errors which occurred during DNA replication if a cell has DNA mutations or errors these checkpoints will stop the cell from entering mitosis in order to give the cell time to fix the errors if the errors cannot be fixed then these checkpoints will cause the cell to die via apoptosis this mechanism ensures that only cells with no DNA mutations are allowed to undergo cell division these quality control checkpoints are carried out by a family of proteins called cyclin and cyclin dependent kinases or ckds cyclin are proteins which bind to enzymes called cyclin dependent kinases there are various kinds of cyclin and ckds which function in different parts of the cell cycle cyclin are called cyclin because they're expression and therefore intracellular concentration Cycles throughout the cell cycle you will see what I mean in the next slide there are various kinds of cyclines and ckds which function in different parts of the cell cycle when a cycl binds to a CKD it forms a structure which is known as a cycl CKD complex this complex then activates the proteins which are required to advance the cell past a checkpoint and ultimately undergo mitosis and cell division so in this graph the concentration of the different cyclin is represented by the Y AIS while the phases of the cell cycle are represented by the x axis as you can see each type of cycl increases concentration depending on the phase of the cell cycle which the cell is in Pay particular attention to the cycl E this cycl is involved in mediating the most important of the cell cycle checkpoints the g1s checkpoint this is the checkpoint which allows the cell to progress from the G1 phase to the S phase we will talk about this checkpoint in just a minute let's talk a little bit about cyclindependent kinases or ckds ckds are enzymes which activate proteins required for cell division and progression through the cell cycle and its checkpoints ckds activates these proteins by phosphor or attaching a phosphate group to certain domains on the protein however ckds alone cannot accomplish this in order for them to successfully phosphorate proteins and activate them they must first interact with a cycl to form a cycl CKD complex in order for this to occur cyclin must be present in the the intracellular space okay so now that we have a basic understanding of cyclin and ckds as well as the cell cycle let's talk about the different cell cycle checkpoints I have highlighted some of the most important and best understood cell cycle checkpoints and included them in this slide however you need to realize that there are many more cell cycle checkpoints of these three the ones which you are most likely to encounter in the USMLE step one is the g1s checkpoint and to a lesser extent the g2m checkpoint in this lecture we will focus primarily on the g1s checkpoint however I will briefly talk about the g2m and spindle checkpoint what you need to know about the g2m checkpoints is that it occurs right after DNA replication and before mitoses the main purpose of this checkpoint is to ensure that any potential DNA eror that occurred during replication are repaired before mitosis all that I will say in regards to the spindle checkpoints is that it occurs in mitosis rather than interphase specifically it occurs between metaphase and anaphase this checkpoint ensures that all of the cell chromosomes are positioned correctly okay so now let's talk about the g1s checkpoint as the name suggests this checkpoint occurs between the transition from G1 to S this is the checkpoint at which the cell chooses whether to undergo mitosis and divide or not divide and instead go into the g0 phase or the resting phase this checkpoint is primarily mediated by a specific cyclin CKD complex called the cycl E ckd2 complex and two important cell cycle regulatory proteins called retinoblastoma protein or RB and e2f so what is the specific function of retino gloma protein and why is it so important the primary function of RB is to prevent excessive cell division by inhibiting cell cycle progression when the appropriate signals for cell division are present AKA cyclin RB is inactivated by phosphorilation RB is normally bound to a transcription Factor called e2f and what I mean by normally is when the cell is not actively dividing once these conditions are right and the Cy e ckd2 complex forms it phosphates RB which causes it to release e2f e2f is an important transcription factor which upregulates the expression of the proteins required for DNA replication and transition to the S phase once e2f is released it is able to bind the promoter of genes which code for DNA replication enzymes such as DNA polymerase here we have a graphical illustration of this process so why is the retinol blastoma protein so important well as you can already imagine if you have a mutation in the gene which codes for the RB protein you may have a complete loss of the function of RB therefore e2f will have nothing to bind to and will constantly activate transcription for proteins required for DNA replication and cell division as a result cells with this mutation will constantly divide and as you already know uncontrolled cell division is the principle behind cancer the RB protein and Gene were named after the tumor which it is associated with retinol blastomas homozygous loss of function mutations in the RB Gene that is mutations which lead to loss of function of the RB protein in both copies of chromosome 13 can lead to the development of a type of cancer called retinol blastoma this cancer is characterized by a malignant tumor of immature retinal cells and it occurs exclusively in children the classic presentation of this disease is lucco Coria or white appearance of the pupil in photographs while this is the tumor which comes to mind when we talk about RB it is not the only tumor associated with loss of function of RB many other kinds of cancers are associated with mutations and loss of function of RB including bladder cancer cangro carcinoma lung cancer and breast cancer the RB Gene is present in every type of cell and depending on the cell where the mutation occurs this dictates what kind of tumor will develop with this in mind this is an excellent time to introduce an extremely important topic known as tumor suppressor genes what are tumor suppressor genes tumor suppressor genes code for proteins which function to control cell division and ensure that it only occurs when necessary mutations which lead to loss of function of tumor suppressor genes increase the risk of cancer by increasing the risk of uncontrolled cell division in essence tumor suppressor genes code for proteins which ensure that cells do not divide out of control and only when required so with this in mind let's finish off with the discussion of the most important tumor suppressor Gene known p-53 p-53 is so important in PR venting cancer and DNA mutations that it is sometimes referred to as the guardian of the genome p-53 in conjunction with other proteins ensures that only cells free of DNA errors can undergo cell division similarly to RB however p-53 functions in both the g1s checkpoint the g2m checkpoint as well as other checkpoints not discussed here p53 works by inducing p21 which is a protein which inhibits all cycl cdk complexes and as we said before without cycling cdk complexes the cell cannot progress through the cell cycle and undergo cell division if a cell contains DNA errors p-53 will either arrest cell division until the DNA has been repaired or it will trigger apoptosis of that cell loss of p53 leads to accumulation of DNA mutations and eventually cancer in fact almost 50% of all malignant tumors have mutations in p-53 so with that we enter discussion of the cell cycle and the regulation of the cell cycle thank you for watching and see you next time