Taipei Medical University, we are proud :D

TMU rank 105 worldwide in life science and medicine category. Congratulations for your achievement.. Keep teaching excellence..!!
http://www.topuniversities.com/university-rankings/world-university-rankings/2011/faculty-area-rankings/life-science-biomedicine?page=2

menuntut ilmu

Kali ini saya pengen membagi kisah tentang betapa beruntungnya kita saat diberi kesepatan oleh Allah untuk hidup di lingkungan akademik, akademisi. Betapa beruntungnya kita (saat ini) berhabitat di kampus, sebuah suaka keilmuan. Akademisi pada hakikatnya adalah majelis ilmu, sekumpulan para penuntut ilmu. Dan sejauh yang saya ketahui, begitu banyak keutamaan golongan ini. Salah satu di antaranya adalah sebuah hadits yang diriwayatkan Imam Abu Daud, Imam Tirmidzi dari Abu Darda’ yang menyebutkan bahwa Rasulullah shallallahu alaihi wasallam bersabda,

مَنْ سَلَكَ طَرِيقًا يَطْلُبُ فِيهِ عِلْمًا سَلَكَ اللَّهُ بِهِ طَرِيقًا مِنْ طُرُقِ الْجَنَّةِ وَإِنَّ الْمَلَائِكَةَ لَتَضَعُ أَجْنِحَتَهَا رِضًالِطَالِبِ الْعِلْمِ وَإِنَّ الْعَالِمَ لَيَسْتَغْفِرُ لَهُ مَنْ فِي السَّمَوَاتِ وَمَنْ فِي الْأَرْضِ وَالْحِيتَانُ فِي جَوْفِ الْمَاءِوَإِنَّ فَضْلَ الْعَالِمِ عَلَى الْعَابِدِ كَفَضْلِ الْقَمَرِ لَيْلَةَ الْبَدْرِ عَلَى سَائِرِ الْكَوَاكِبِ وَإِنَّ الْعُلَمَاءَ وَرَثَةُ الْأَنْبِيَاءِ وَإِنَّالْأَنْبِيَاءَ لَمْ يُوَرِّثُوا دِينَارًا وَلَا دِرْهَمًا وَرَّثُوا الْعِلْمَ فَمَنْ أَخَذَهُ أَخَذَ بِحَظٍّ وَافِرٍ

“Barangsiapa yang menempuh perjalanan untuk mencari ilmu, niscaya Allah subhanahu wata’ala menyediakan jalan untuknya menuju surga. Sesungguhnya para malaikat melebarkan sayapnya karena ridha kepada orang yang menuntut ilmu. Sesungguhnya ulama dimintakan ampun oleh makhluk yang berada di langit dan di bumi sampai paus yang di dalam laut. Keutamaan seorang alim atas seorang abidseperti keutamaan bulan atas segala bintang. Sesungguhnya ulama itu adalah pewaris para nabi. Sesungguhnya para nabi tidak mewariskan dinar dan dirham, tetapi mereka hanya mewariskan ilmu. Barangsiapa yang mengambil ilmu itu, maka sungguh dia telah mengambil keberuntungan yang banyak.”

Lihatlah begitu mulianya golongan berilmu dan penuntut ilmu (dalam istilah FK mungkin Guru/Dosen dan mahasiswa) yang termaktub dalam hadits tsb. Allah, malaikat dan seluruh makhluk di langit dan bumi ridho kepadanya. Dari hadits ini juga tampak keutamaan bagi dua golongan, yaitu para penuntut ilmu dan para ulama (orang yang berilmu). Pada penuntut ilmu, Allah meridhoi jalannya dan membuka jalannya menuju surga, balasan atas usahanya belajar. Malaikat bahkan membentangkan sayapnya untuk dia berjalan di atasnya menuju majelis ta’lim, tempat ia menuntut ilmu. Majelis ta’lim ini bisa di mana saja, ruang tutorial, ruang kuliah, taman medika, atau mungkin masjid ibnu sina (kalo kita ngobrolin hal2 yang merupakan bagian dari menuntut ilmu). Untuk golongan kedua, para ulama bahkan Rasulullah memberinya gelar yang mulia yaitu pewaris para nabi. Sebagai bentuk keutamaan dan apresiasi atas perannya yang begitu penting. Karena hakikat dari guru/ulama ini adalah menyampaikan ilmunya, mewariskan ilmunya kepada generasi berikutnya. Ilmu inilah yang akan membentuk generasi berikutnya yang lebih baik, lebih mulia, dan itulah salah satu ciri ilmu yang barokah. Membawa kebaikan yang terus menerus.

Sebagai penuntut ilmu

Sebagai penuntut ilmu alias mahasiswa, saya masih inget betul pertama kali saya dianggap sebagai golongan ini (tahun 2004, jaman saya masih muda.. hehe..). Saat itu salah satu guru saya mengingatkan, jika suatu saat kamu lelah atau merasa jenuh dengan belajarmu maka ingatlah betapa banyak anak seumurmu di luar sana yang bermimpi menjadi sepertimu. Berada disini berpredikat sebagai mahasiswa kedokteran. Pastilah Allah memiliki maksud yang baik mengapa Dia memilihmu, bukan ribuan yang lain yang tidak ada disini. Kalimat ini menjadi bagian dari kalimat yang ampuh memotivasi saya di saat2 jenuh, atau merasa sangat jatuh. Maka bagian penting dari penuntut ilmu adalah menumbuhkan motivasi. Carilah seribu alasan untuk kita terus belajar. Itu bisa apa saja, kita bisa mengingat perjuangan keras kedua orang tua kita untuk menyekolahkan kita. Bagaimana beliau bangun di pagi hari, saat kita masih terlelap, tidak hanya menyiapkan nafkah dan materi bagi kita tetapi juga kasih sayang dan pengharapan hingga sekarang. Atau kita bisa mengingat bagaimana kerasnya kita belajar untuk bisa lulus SNMPTN misalnya. Atau apapun itu selama itu adalah motivasi yang baik, dan sebaik-baik motivasi pada akhirnya adalah mendapatkan Ridho Allah SWT. Maka luruskanlah niat, kuatkan motivasi kita.

Tentunya perjalanan penuntut ilmu ini tidak semulus jalan tol, nggak selembut bakpao (jayus ah, hehee...). Banyak tantangan, banyak cobaan di depannya. Tapi itulah hakikat dari perjuangan menuntut ilmu. Tidak perlu banyak mengeluh, anggep aja sebagian dari ujian ini akan menambah perjuangan menuntut ilmu dan menjadi bagian dari ibadah. Kalo tentamen itu misalnya dianggap sulit, tidak perlulah mengeluh karena sulitnya. Dinikmati aja, kalo nggak sulit ga ada seninya mungkin,hehee... Bisa jadi kesulitan itu sebenernya juga karena mindset kita yang menganggap sulit, dan semakin besar karena kita semakin mengeluh. Pastinya bersama kesulitan itu ada kemudahan, dan buktinya dulu2 pun saat jaman kurikulum belum berbasis kompetensi semua dokter UGM itu juga pernah tentamen (tentunya dengan kebijakan dan ujian yang lebih horor), dan mereka bisa melaluinya dengan baik. Maka yang kedua adalah jangan mudah mengeluh.

Kemudian kalo kita ingat dan niatkan perjalanan menuntut ilmu ini sebagai ibadah maka ingatlah beberapa adab menuntut ilmu. Kira-kira pantas gak kalo orang beribadah dengan pakaian yang kurang sopan misalnya. Ke kampus misalnya pake pakaian kaya ke mall (atau kostum dugem, masya Allah), aurat dimana2. Bisa jadi itu penghalang disampaikannya ilmu kepada kita. Sebenarnya kita pantas bersyukur, karena budaya ketimuran kita memfasilitasi kita untuk lebih santun dalam berpakaian dan bersikap. Tapi di atas dari semua itu agama sesungguhnya sudah mengatur kehidupan dengan begitu agung. Karena sebenernya agama itu adalah aturan hidup di dunia, bukan aturan hidup di akhirat. Maka hiasi setiap kehidupan akademik kita dengan warna yang Islami, sebagai bagian dari adab menuntut ilmu.

Bagian dari hadits tersebut di atas juga mengisyaratkan keutamaan para ulama (termasuk di antaranya adalah guru-guru kita). Menghormati mereka adalah bagian dari adab menuntut ilmu. Rendah hati dan menghormati guru kita sebagai orang yang berilmu. Hormatilah secara proporsional saja, sebagai bentuk penghormatan misalnya dengan tersenyum saat bertemu, menyapa dan berucap salam. Dulu jaman saya masih SD ada kebiasaan yang sekarang mungkin sudah jarang ditemui, saat guru kita ‘rawuh’ semua anak tanpa ada yang mengkomando langsung menyerbu untuk segera menyapa dan mencium tangan beliau. Meskipun metode ini tampaknya kurang feasible untuk diaplikasikan di kampus, tetapi bentuk menghormati guru tetap bisa dilakukan dengan cara yang lain.Maka selalu hormatilah guru kita.

Yang terakhir mungkin saya ingin mengingatkan diri sendiri adalah untuk tetap rendah hati, kepada siapapun, termasuk kepada ilmu itu sendiri. Rendah hati terhadap ilmu berarti tidak merasa cukup dan sombong atas ilmu yang sementara ini sudah Allah berikan. Karena dengan merasa tinggi hati akan hilanglah rasa ingin tahu. Padahal curiousity adalah kunci ilmu pengetahuan. Ga akan ada hukum newton kalo Isaac Newton tidak ingin tahu kenapa apel itu jatuh kebawah, misalnya. Rendah hati kepada ilmu juga akan mengantarkan kepada motivasi dan konsistensi menuntut ilmu. Saya pernah miris saat suatu ketika menemui kelas skills lab hanya dihadiri oleh 4 orang dari 10 mahasiswa di grup itu. Yang menjadikan miris waktu itu adalah bukan karena kejadian itu sebagai insiden, tetapi merupakan tren karena saya menemuinya beberapa kali. Padahal saya yakin dari 6 anak yang tidak hadir itu tidak satupun yang punya fasilitas gedung skills lab lengkap dengan alat dan instrukturnya. Dengan kata lain, seandainya mereka merendahkan hatinya dan datang ke majlis ta’lim skilleb (wah istilah baru ni,hehee...) mereka bakal mendapatkan sesuatu yang berguna. Adult learner sebenarnya bukan alasan untuk tidak menghadiri kegiatan akademik yang dijadwalkan. Lebih dari itu adult learner harusnya mengambil pelajaran lebih dari yang dijadwalkan, di luar jadwal akademiknya. Maka yang terakhir adalah ikhlaskanlah diri kita untuk mau diajar, rendah hati dan bersiap untuk mendapatkan ilmu yang bermanfaat. Karena saya yakin, guru-guru kita itupun telah mengikhlaskan hatinya untuk mau mengajar kita dengan baik.

Sementara ini dulu yang ingin saya bagikan, semoga saya yang sekarang juga lagi jadi penuntut ilmu teringat untuk lebih oke lagi sebagai penuntut ilmu.. Kalo ada kesempatan mungkin akan ada berbagi pengalaman tentang keutamaan sebagai guru, hehe...

Rabbi zidni ‘ilman war zuqni fahman

“Ya Rabb tambahkanlah ilmu (kepadaku) dan Rizqikanlah pemahaman”

Dalam kitab Ibnu Abdil Barr, yang dimaksud dengan alim adalah golongan berilmu, yang lebih banyak benarnya daripada salahnya. Kalo mengingat hal ini maka tentu saja sebagai guru tetaplah Ia belajar, biar apa yang ia ucapkan lebih banyak benarnya. Tentunya apa yang ia pelajari akan lebih banyak dari yang sang murid pelajari, karena ibarat mata air ia akan mengalirkan airnya ke sungai-sungai. Maka bagaimana mungkin bisa mengalirkan air ke sungai2 kalo ia tidak lagi memperkaya dengan mata air ilmu. Sebagian dari keutamaan para ulama sudah termaktub dalam keutamaan penuntut ilmu karena para ulama sejatinya juga penuntut ilmu, juga selalu menuntut ilmu dan lalu membagikan apa yang ia ketahui.

sebagian ulama memisahkan antara meuntut ilmu agama dan ilmu umum. tetapi keduanya tetap wajib hukumnya bagi orang muslim. 

Cancer Metastasis: The invasiveness of Cancer Cells

Cancer becomes a global problem because of its high mortality and morbidity. The higher mortality rate of cancer patients relatd to their metastasis capacity. This lecture will present recent advances in understanding of metastasis and cancer invasion.

Main steps of cancer metastasis start from angiogenesis of primary tumor. Then, several  cancer cells will invade or detach vascular wall to enter circulation system. In this phase cancer cells form emboli, may interact with platelets or other component of blood. Heart pumps cancer cells containing blood into target organ. In target organ, cancer cells attach to vessel wall and extravasation. Cancer cells develop microenvironment to support their viabilty.

1.       Tumor angiogenesis

Tumor angiogenesis is establisment of new blood vessels that penetrates into cancer tissue. This blood vessels are very important to supply nutrients and oxygen and remove waste products. Cancer cells release some signaling molecules to normal tissue which encourage growth of new blood vessels. The major mediator of angiogenesis is Vascular Endothelial Growth Factor A (VEGF A). VEGF A expression is stimulated by epigenetic (hypoxia, cytokines, growth factor, sex hormone and chemokines) and genetic factors. VEGF A bind to VEGF R1, VEGFR2 or NRF2 receptor. This binding activate PI3Kinase-Akt pathway to promote cell survival. VEGF A and VEGFR2 also activate some other pathways that support cancer cells capacity in migration, mobilization, proliferation and vascular permeability.

Some research investigated role of Endothelial-Cell–Associated Deltalike Ligand 4–Notch signaling pathway in angiogenesis. Dll4 binds to notch receptors that are expressed in the vascular endothelial cells composing the “stalk” component of a growing capillary sprout, adjacent to the tip cells. This result emphasize combination of anti-VEGF drug and DII4 targeting drug has better efficacy.

2.       Invasion or metastasis properties

Cancer cells can detach vessel wall, firstly they will detach lymphatic vessel wall. Interconnection of lymphatic and blood vessels make cancer cells possible to enter circulatory system. Several mechanism promote metastasis properties of cancer cells.

-         
Adhesive capacity

Cancer cells have less adhesive capacity of each other, thereby allows cancer cells to seperate from the main tumor mass. In many cases, loss of adhesiveness is corelated with E-cadherin decrease. E-cadherin is binding protein that binds epithelial cells one another.

-          Epithelial Mesenchymal Transition (EMT)

EMT is character change of cancer cells which make them more invasive, from epithelial characters change to mesenchymal characters. E-cadherin is an important adhesion molecule that support adhesiveness. It connects adheren junction in cell surface and Cathenin protein in cytosol. Less E-cadherin will increase Beta cathenin intracytoplasmic. Free Beta cathenin bind some target genes, such as Myc, Cyclin, TCF-1, MMP etc. Activation of target genes lead to migration enhancement and adhesion reduction.

The importance of EMT stimulates researchers to find out transcription factors responsible for EMT.

Name	Where first identified	Type of transcription factor	Cancer association
Slug	Determination of the neural crest and early mesoderm in chicken	C2H2 type zinc finger	Breast cancer lines; melanoma
Snail	Mesoderm induction in drosophila/neural crest migration in vertebrates	C2H2 type zinc finger	Invasive ductal carcinoma
Twist	Mesoderm induction in Drosophila; emigration from neural crest	bHLH	Invasive lobular carcinoma, high grade melanoma and neuroblastoma

Biochemical analysis shows increase of mesenchymal-state proteins and decrease of epithelial-state protein. Some proteins that increase are: fibronectin, vimentin, N-catenin, and srn-actin. Proteins that decrease are: E-cadherin, alfa catenin, beta catenin and gamma catenin.

It is likely that EMT triggered by mixture of signals from stromal and intracellular (such as: ras oncogene). Combination of signals cause loss of epithelial adheren junctions and cellular polarity. In the other hand, combination of signals trigger cellular motility, invasiveness and protease secretion that support cancer metastasis.

-          Cell Motility

Cellular motility is activated by signaling molecules. After the loss of cell-cell adhesion, cancer cells migrate to other place with guidance of these signaling molecules as chemoattractant.

-          Secretion of proteases to degrade structures that limit cancer cells movement. One of important protease in cancer metastasis is plasmin proteases. Plasmin is converted from precursor plasminogen by converting enzyme, plasminogen activator. Plasminogen activation is catalyzed by urinary (uPA) or tissue-type Plasminogen Activator (tPA). uPA known as an important factor in cell migration and invasiveness, such as cancer metastasis. After plasminogen being activated to form plasmin, this protein can degrade basal lamina and extracellular matrix. Plasmins also activate matrix metalloproteinase by cutting of its tail.

3.       Circulating cancer cells

Cancer cells may be deposited as homotypic clusters that lodge in narrow capillaries due to size restriction. Cancer cells also have capacity to form emboli, associated with platelets and leukocyte, form projection to enhace adhesive capacity to vessel wall. cancer cells-platelets emboli then adheres endothelial cells by interaction with L-selectin ligand. Interaction with endothelial cells initiate extravasation process into target organ

4.       Target organ

Cancer cells have special affinity for microenvironment of target organ. Cancer cells ability to grow is related to molecules present in the target organs. Certain molecules are needed by cancer cells, so that some cancer cells have specific location to spread. For example, prostate cancer probably spread to brain, lung, bone marrow and liver.

Overview of novel findings in cancer metastases: VEGFC/VEGFR3

VEGFR3 and VEGFC interaction contribute in invasiveness of multiple cancer types. VEGFr3 is receptor that may influence cell migration and cell proliferation through multiple pathways: PI3Kinase, Src and PLC-gamma. VEGFC contributes as ligand that bind to VEGFR2. Their interaction also enhances metastases properties by lymphangiogenesis promotion through JNK1/2, AKT or ERK pathway.

What is cancer?

Cancer becomes a global problem, so that many researchers focus on this issue. Some researcher also won nobel prizes for their works in this field because of their important finding. To help us understand about recent advances in cancer research this lecture brings an overview of cancer.

Cancer is defined by their character of abnormal cells that divide without control and be able to invade other tissue. Invasiveness is cancer capacity to spread to other parts of the body. This capacity is mediated through lymph and blood vessel. So cancer cells can spread to distant place.

Classification

Hundreds type of cancer have been discovered recently. Basically, they named by their first affected organ:

-          Carcinoma   : cancer that begins in the skin or tissue that cover (line) internal organ.  Histological character of this type is epithelial.

-          Sarcoma       : cancer that starts from connective tissue, such as bone, fat, cartilage, muscle, blood vessel.

-          Leukemia    : cancer that starts from blood-forming tissue that produces abnornal blood cells

-          Lymphoma and myeloma : cancer that affects immune system cells

-          Central nervous system cancer : cancer that begins from central nervous system, brain and spinal cord.

Generally, Naming of cancer always begin with tissue origin and followed by cancer type as mentioned above. For example cancer that originated in striated muscle tissue is called rhabdomyo sarcoma. Further, each cancer type will be classified into several subtypes for clinical importance, Bethesda classification system for cervical cancer etc. In clinical setting they also classified based on stage and grade difference.

Cancer pathology is started from abnormal cell, the basic functional unit of human body. Understanding cellular pathology in cancer formation is essential to design treatment strategy. Normally, human body is composed by many types of cell that grow, divide, and death in controlled mechanism. However, sometimes this process is interrupted. Genetic material of the cells, the DNA, can be damaged by many environmental factors. This event leads to interruption of cell division or cell death. They may divide without control and do not die when they should. So that, these new cells will form an abnormal mass which is called a tumor.

Cancer treatment

Actually tumor means enlargement of tissue, in this case because of increment of cell number. So, not all tumor is cancerous. Some of tumors are benign tumor. Benign tumors are differentiated to the malignant one on their invasiveness. Benign tumors do not spread to other tissue. This tumor will ‘stay’ in their origin tissue and cause mass effect because of enlargement, but none of them can spread to other tissue. So that, benign tumor can be evacuated by surgical procedure only. In the other hand, malignant tumor (cancerous) has capacity to spread to other tissue involving lymphatic or blood vessel (metastasis). That’s why in certain stage of cancer they can’t be eradicated by surgical procedure only. In spite of surgical treatment, today another available treatment modalities are chemotherapy, radiotherapy and immunotherapy.

Overview of treatment modalities

Therapy	Brief explanation
Chemotherapy	Chemotherapy is treatment option that uses drugs to destroy cancer cells. The drug affects cancer cells and other cells that divide quickly. Chemotherapeutic drugs may cure cancer, control cancer cell division or ease cancer symptoms. Example: cisplatin (alkylating agent), taxol (antimicrotubule drug)
Radiotherapy	Radiotherapy is given by transferring the beam of ionizing radiation. Radiation of gamma rays and X-rays can be focused to target organ, where the cancer cells reside. Radiation beam is produced by radioactive particle (for example Cobalt-60) in the cyclotrone. Anather way to transfer the radiation is using implant (sealed source radiotherapy) that present very close or inside the tumor. It is called brachytherapy (brachy means near). Brachytherapy commonly used to treat Nasopharyngeal cancer.
Immunotherapy	Immunotherapy can be delivered in two ways: stimulating patient’s immune system to reject cancer cells, or administration of antibody in which case the patient’s immune system is recruited. Many monoclonal antibodies have been developed recently, for example: Rifuximab, Cetuximab etc.

Concept of personalized medicine in cancer patient

Understanding of molecular basis in cancer pathology will give a complete perspective of the disease. Thus support a better treatment strategy, and also the discovery of novel treatment. In Taiwan, The National Cancer Institute (NCI) is developing a concept of personalized treatment based on the biology of individiual patients and their cancers. Not only focus on prevention, diagnosis and treatment, NCI also develop approaches to predict how individual may respond to any given treatment based on molecular biology.

By definition, personalized treatment means  a medical model emphasizing in general the customization of healthcare, with all decisions and practices being tailored to individual patients in whatever ways possible. It mainly involves the systematic use of genetic or other information about an individual patient to select or optimize that patient's preventative and therapeutic care. A revolutionary concept of personalized medicine in cancer promises a better therapeutic approach, improve patient outcome and reduce unnecessary treatment. First targeted therapy intruduced was Herceptin for breat cancer treatment. Herceptin is antibody targeted to HER-2. Herceptin combined to chemotherapy effectively reduces reccurance in patients who have specific gene. It means that breast cancer is not a single disease, it’s consists of many subtypes that also need different therapeutic way for optimal cure.

Some of important targets to control cancer cells are cell cycle control and apoptosis. Cell cycle is very important because it is about cell determination, to divide, to stop growing, or to resting cell. Cell cycle mainly divided into two phase: M (mitotic) phase and Interphase (consists of G1, S and G2 phase). In order to determine the progression of cell cycle, there are three check points that will be a critical point to decide the completion of cell cycle. It is just like an ON-OFF switch. Cyclins are proteins that take part in these checkpoint. It binds to Cdk and activate the Cdk active site. Inactivation of Cyclin-Cdks complex may stop the progression of cell cycle. It gives hope in cancer treatment.

In other part, apoptosis also an important issue in cancer treatment. Apoptosis is an integral part of development to maintain homeostasis, in this case to maintain dynamic equilibrium of cell number. If apoptosis is disrupted, cell fail to die then lead to development of tumor. Therefore, cell division and apoptosis should be maintained in a balanced rate. Another way to manage cancer cells is turning on the apoptosis pathway, the caspases pathway. Once caspase is activated, it will become an explosive destroyer that lead cell death.

Ubiqitination Mediated-Protein Degradation - (lecture note edition)

Ubiquitin mediated-protein degradation is one of the most important pathway in intracellular protein degradation. The discovery of this system, that been called Ubiquitin Proteasome System (UPS), was awarded a Nobel prize in 2004. It is because of their importance in orchestrating many protein degradation. Thus, will control the protein level that regulate many diverse action.

Protein undergoes degradation to maintain its dynamic level following the synthesis. So that, the protein turnover (degradation and resynthesis) must be tightly controlled to achieve the dynamic balance. Intracellular protein degradation (proteolysis) should be maintained spesifically and selectively because each Intracellular protein has different half life that vary from minutes to days. Some of them needs special signaling pathway.

There are three type of protein degradation in mammals (summarized in the table below)

type	Explanation
Digestion of dietary protein in the gut and absorption of amino acids	This is the process of ingested protein degradation (external protein). After degraded mechanically, the proteins will be degraded enzymatically into their absorbable form (amino acids). Some protease enzymes have pivotal role in this protein degradation, such as: endoprotease that cleave protein backbone (trypsin, chymotrypsin), exopeptidase that remove residues from N-terminus to C-terminus (carboxypeptidases), and peptidase that split oligonucleotide to smaller absorbable nucleotide or amino acids. These enzymatic mechanisms occured in the different part of gut.
Degradation of extracellular protein	It is one of degradation system for body’s own protein. It is mediated by lysosomal degradation system. This system degraded all extracellular protein and 20% of intracellular proten. Some extracellular proteins that be degraded by this pathway are: LDL, peptide hormone and cell surface membrane protein.
Degradation of intracellular protein	Degradation of intracellular protein mainly mediated by Ubiquitin Proteasome System (UPS). Almost all intracellular protein (80%) normally degraded by this pathway, especially intracellular proteins which have short half life.

In this lecture we will focus on intracellular degradation system.

Lysosomal degradation system

Lysosome is one of organelles within cell which is produced by golgi apparatus. Lysosome contains enzymes: carbohydrases, lipases, nucleases, and proteases. These enzymes are very important in the degradation of  waste materials, cellular debris, excess or worn-out organelles and invaded microorganisms. Lysosome can digest many particles that enter cell. Some solid particles can be digested after endocytosis, for example membrane bound protein. Pinocytosis will mediate digestion of some non-specific extracellular protein. After pinocytosis, the extracellular protein will be covered by a mantle from cell membrane and then digested by lysosomal enzymes. Lysosome can digest proteins within cell by autophagy mechanism, for example digestion of warn-out organelles.

Ubiiquitin Proteasome System

Ubiquitin Proteasome System (UPS) has important role in many cell process by degrading specific intracellular protein that takes part in specific process, such as cell growth, cell differentiation, cell cycle, signal transduction etc. UPS also has function in degrading misfolded protein, mislocated protein or mutant protein. Because of its importance in many intracellular proteins, any malfunction of UPS may leads to pathological condition. For example, malfunction of UPS in degradation of tau protein that leads to Alzheimer’s disease.

Mechanism of UPS can be divided into two major process: ubiquitination and proteolysis.

1.      

Ubiquitination

Ubiquitination is a process of ubiquitin conjugation to mark the spesific protein that want to be degraded. Ubiquitination process can be summarized by the figure below:

By this figure we can see that inspite of Ubiquitin (Ub), UPS also needs  three important protein: E1, E2, and E3. E1 is an ubiquitin activating enzyme that will activate Ubiquitin in its C-terminus. The activated ubiquitin then will be transferred to E2 (Ubiquitin conjugating enzymes). Finally ubiquitin will be attached to target protein by E3 (ubiquitin-protein ligase). It needs polyubiquitin chain (at least 4 ubiquitin) to be transferred to target protein before these protein becomes degradable. Mammalian has so many E3 types, more than 1000, that gives them capacity to degrade many intracellular proteins. Big number of E3 types makes them very interesting to be explored.

E3 has three mechanisms to transfer ubiqitin toward target proteins.  There are constitutive recognition, modification and association with an ancillary protein. Constitutie recognition allows the substrate to be recognized without any previous alteration and are degraded at the same rate of different condition. In other case, target protein (substrate) should be modificated before attach E3, for example: phosphorylation of IkBα. In the third mechanism, targeted protein should attach ancillary protein before being transferred to E3. For example, the association of p53 and HPV oncoprotein E6.

2.       Proteolysis

Protein degradation in UPS needs 26S proteasome (deubiquitinating enzymes). Next Ubiquitin as a tag is going to be recycled for reubiquitination. Proteins are tightly controlled in this degradation system. They should have spesific recognition structure. Short-lived proteins have Arg, Lys, Phe, Leu, or Trp at their N-terminus. They will be degraded within 3 minitues in vivo. In the other hand, proteins that have Cys, Ala, Ser, Thr, Gly, Val, or Met is present at their N-terminus will be degraded within 30 hours. It leads them become long-live proteins. Degradation of labelled protein occured in 26 S proteasome.

26 S proteasome is assembled from core unit (20S) and regulatory unit (19S). Core unit is composed by two identical alfa ring and two outer Beta ring. Core unit function is as a catalytic center that degrade protein into small peptide followed by release of reusable ubiquitin via deubiquitination enzyme. The 19S regulatory unit is also an important part. It has several function in binding to polyubiquitinated protein, unfolding the peptide chain, opening the access port in the outer ring, and transferring the unfolded protein into catalytic center.

Beside their capacity to degrade many intracellular proteins, proteasomes also contains deubiqutination (DUB) enzymes which are key regulators for ubiquitin-mediated pathways. DUB has diverse action, such as:

-          Recycling the ubiquitin.

This function is facilitated by cysteine proteses that catalyze polyubiquitine cleavage into reusable ubiquitin monomers.

-          Regulation of protein degradation.

It consists of editing and reversal of ubiquitin chains.

-          Ubiquitin biosynthesis.

DUB will remove ubiquitin with additional C terminal residue to expose C terminal glysine that has active site.

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