Transition and identification of pathological states in p53 dynamics for therapeutic intervention

AbstractWe study a minimal model of the stress-driven p53 regulatory network that includes competition between active and mutant forms of the tumor-suppressor gene p53. Depending on the nature and level of the external stress signal, four distinct dynamical states of p53 are observed. These states can be distinguished by different dynamical properties which associate to active, apoptotic, pre-malignant and cancer states. Transitions between any two states, active, apoptotic, and cancer, are found to be unidirectional and irreversible if the stress signal is either oscillatory or constant. When the signal decays exponentially, the apoptotic state vanishes, and for low stress the pre-malignant state is bounded by two critical points, allowing the system to transition reversibly from the active to the pre-malignant state. For significantly large stress, the range of the pre-malignant state expands, and the system moves to irreversible cancerous state, which is a stable attractor. This suggests that identification of the pre-malignant state may be important both for therapeutic intervention as well as for drug delivery.

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Cancer Dynamics: Identification of States for Therapeutic Intervention

10.20944/preprints202005.0063.v1 ◽

2020 ◽

Author(s):

Amit Jangid ◽

Md Zubbair Malik ◽

Ram Ramaswamy ◽

R. K. Brojen Singh

Keyword(s):

Therapeutic Intervention ◽

Regulatory Network ◽

Suppressor Gene ◽

External Stress ◽

Stable Attractor ◽

Stress Signal ◽

Malignant State ◽

Dynamical Properties ◽

Mutant Forms ◽

Dynamics Identification

We study a minimal model of the stress-driven p53 regulatory network that includes competition between active and mutant forms of the tumor-suppressor gene p53. Depending on the nature of the external stress signal, four distinct dynamical states are observed. These states can be distinguished by dierent dynamical properties and correspond to active, apoptotic, pre-malignant and cancer states. Transitions between any two of these states are found to be unidirectional and irreversible if the stress signal is either oscillatory or constant. When the signal decays exponentially, the apoptotic state vanishes, and for low stress the pre-malignant state is bounded by two critical points, allowing the system to transition reversibly from the active to the pre-malignant state. For signicantly large stress, the range of the pre-malignant state expands and the system moves to the cancerous state which is a stable attractor. This suggests that identification of the pre-malignant state may be important both for therapeutic intervention as well as for drug discovery.

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Mutational analysis of a dominant oncogene (c-Ki-ras-2) and a tumor suppressor gene (p53) in hamster lung tumorigenesis

Molecular Carcinogenesis ◽

10.1002/mc.2940060305 ◽

1992 ◽

Vol 6 (3) ◽

pp. 199-202 ◽

Cited By ~ 11

Author(s):

Victor I. C. Oreffo ◽

Hsiu-Wei Lin ◽

Paul H. Gumerlock ◽

Susan A. Kraegel ◽

Hanspeter Witschi

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Mutational Analysis ◽

Suppressor Gene ◽

Lung Tumorigenesis ◽

Tumor Suppressor Gene P53

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Given the importance of mTOR signaling in a number of illnesses, it looks suitable to use miR 99 family members as a therapeutic intervention to deal with these illnesses by using gene therapy tools

10.31219/osf.io/8cwgh ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Therapeutic Intervention ◽

Regulatory Network ◽

Immune Cell ◽

Family Members ◽

Cell Activity ◽

Mtor Signaling ◽

Critical Pathways ◽

Functional Roles ◽

Cell Life ◽

High Level

This review outlines the activities of mirR99 family members in different cancers. Though the functional roles of these miRs are well described in some malignancies, the functional functions of these family members in other forms of cancer remain uncertain. The development and use of engineered mouse models such as miR99a KO, miR100 KO, or miR99a/100 DKO mice challenged with the type or subtype of the cancer in question would be extremely beneficial in determining the physiological and pathological roles of members of this family in different types of cancer and immune cell subtypes.The miR99 family members, which include miR99a, miR99b, and miR100, are key components of a regulatory network that governs several aspects of the cell life cycle, including differentiation, metabolism, survival and death. They are involved in the deregulation of numerous critical pathways including growth factor receptors like FGFR and IGF1R, Notch, mTOR, TGFB and Wnt signaling pathways to alter cellular function. In addition, the typical miR99 target, mTOR, appears to be at the core of the regulatory network miR99, and is more commonly involved in miR99-mediated dysregulation of cell activity. Given the importance of mTOR signaling in a number of illnesses, it looks suitable to use miR99 family members as a therapeutic intervention to deal with these illnesses. mTOR depletion did not result in upregulating miR99a in OSCC cells. In addition, an aberrant activation of PI3K/AKT/mTOR signaling in AMLs, despite increased expression of miR99 family members in AMLs. All in all, this evidence alludes to the existence of an unknown mechanism that maintains mTOR activity running despite the presence in these cells of a high level of miR99 family members. Modulation of miR99 activity might be a viable method for changing the expression of Treg in autoimmune diseases.

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Gene Therapy Clinical Trials for Cancer: Replacement of Tumor Suppressor Gene p53

Gene Therapy ◽

10.1201/9781420002126-45 ◽

2000 ◽

pp. 761-770

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

Tumor Suppressor Gene P53

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Correlation of primary tumor size and axillary nodal status with tumor suppressor gene p53 in breast carcinoma

Vojnosanitetski pregled ◽

10.2298/vsp0201029t ◽

2002 ◽

Vol 59 (1) ◽

pp. 29-32 ◽

Cited By ~ 1

Author(s):

Brano Topic ◽

Nebojsa Stankovic ◽

Dragutin Savjak ◽

Slavko Grbic

Keyword(s):

Prognostic Factors ◽

Breast Carcinoma ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Tumor Size ◽

Primary Tumor ◽

Suppressor Gene ◽

Nodal Status ◽

Primary Tumor Size ◽

Tumor Suppressor Gene P53

Correlation of standard path morphological prognostic parameters, primary tumor size and axillary nodal status with new prognostic factor in breast carcinoma: tumor suppressor gene p53 was analyzed. The studied sample included 65 women who underwent surgery for breast carcinoma at the Surgical Clinic of Clinical Center Banja Luka, from January 1st 1997 till January 1st 1999. Statistical data analysis was performed and correlation of prognostic factors was determined. The majority of authors in this field agree that the primary tumor size and axillary nodal status are the two most important prognostic factors. These factors are the best predictors of prognosis and survival of women who had the tumor and were operated on. Tumor markers were immunohistochemically determined in the last ten years and, according to the majority of authors, are still considered the additional or relative prognostic factors in breast carcinoma. Their prognostic value and significance increase almost daily. Most frequently determined tumor markers are bcl-2, pS2, Ki-67 and p53. There was a positive, directly proportional relationship between primary tumor size and tumor suppressor gene p53, but there was no positive correlation between the axillary nodal status and tumor suppressor gene p53. Significance of determination of new tumor markers as the prognostic factors was emphasized. These markers represent a powerful tool in the early detection and prevention of breast carcinoma.

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